CN116018334A

CN116018334A - Process for preparing 3- (cyclohex-1-en-1-yl) propanal derivatives

Info

Publication number: CN116018334A
Application number: CN202180049653.7A
Authority: CN
Inventors: O·克诺普夫; P·迪波; J-J·雷德豪泽; N·波伊利尔; P·福恩特斯迪尔维尔; A·伯恩纳尔; L·马力诺尼
Original assignee: Firmenich SA
Current assignee: Firmenich SA
Priority date: 2020-09-01
Filing date: 2021-08-30
Publication date: 2023-04-25
Also published as: WO2022049036A2; US20230365523A1; JP2023538721A; MX2023000555A; EP4153552A2; IL299699A; WO2022049036A3

Abstract

The present invention relates to the field of perfumery. And more particularly to a valuable new chemical intermediate for the production of perfuming ingredients. The invention furthermore comprises a process for the production of the compounds of formula (I).

Description

Process for preparing 3- (cyclohex-1-en-1-yl) propanal derivatives

Technical Field

Background

In the fragrance (daily chemical flavour) industry, there is a continuing need to provide compounds that impart new sensory notes. In particular, there is interest in aldehyde notes, which represent one of the key sensory fine notes (facet) of the scent of lilium falciferum (lily of the valley). Thus, there is a particular need for compounds that impart the noted notes to reproduce the subtle floral notes of mugwort (muguet), which cannot survive even the most gentle extraction methods used to produce essential oils. 3- (cyclohex-1-en-1-yl) propanal derivatives represent compounds which confer a note to the olfactory family of muguet-aldehydes, such as 3- (4, 4-dimethyl-1-cyclohexen-1-yl) propanal reported in EP1529770 or 3- [4- (2-methyl-2-propanyl) -1-cyclohexen-1-yl ] propanal reported in EP 1054053. However, the process of obtaining these derivatives is tedious, requiring grignard reagents, free radical chemistry, hydrogenation or pyrolysis of dienal, providing the desired compound in low yields and/or selectivities.

As industrially interesting products, new processes showing improved yields or productivity are always needed.

The compounds of formula (II), formula (III) and formula (IV) which are the object of the present invention have never been reported or suggested in the context of the preparation of the compounds of formula (I). Only a few of the compounds of formula (II) and formula (III) have been reported in the prior art, but none are intermediates in the synthesis of compounds of formula (I).

Thus, the prior art, while reporting some derivatives of formula (II) and formula (III), is not to be considered as implying the present invention.

Disclosure of Invention

The present invention relates to a novel process which allows the preparation of compounds of formula (I) in high yields and selectivities starting from novel compounds of formula (II). The method of the present invention represents a novel and effective route to the compounds of formula (I).

Accordingly, a first object of the present invention is a process for preparing a compound of formula (I),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein each R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently represents a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group; or R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Two groups of (B) together form C _3-8 Cycloalkyl or C _5-8 Cycloalkenyl, the other groups having the same meaning as defined above;

the process comprising a hydroformylation and elimination step starting from a compound of formula (II),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined in formula (I), and X represents a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group.

A second object of the present invention is a compound of formula (III),

the compound is in the form of any one of its stereoisomers or mixtures thereof, wherein X represents a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group; each R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently represents a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group; or R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Two groups of (B) together form C _3-8 Cycloalkyl or C _5-8 Cycloalkenyl, the other groups having the same meaning as defined above; with the proviso that 1- (3-oxopropyl) cyclohexyl acetate is excluded.

Another object of the present invention are compounds of formula (IV'),

The compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein X' is a hydrogen atom, C _1-3 Alkyl, C _2-3 Alkenyl, benzyl or a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group; each R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently represents a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group; or R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Two groups of (B) together form C _3-8 Cycloalkyl or C _5-8 Cycloalkenyl, the other groups having the same meaning as defined above; r is R ^a And R is ^b Each independently represents C _1-4 Alkyl, or R ^a And R is ^b Taken together represent C _2-6 An alkanediyl group; provided that 1- (2- (1, 3-di) is excludedOxacyclopentane-2-yl) ethyl) -4-isobutyl-2-methylcyclohex-1-ol, 1- (2- (1, 3-dioxan-2-yl) ethyl) -4- (tert-butyl) -2-methylcyclohex-1-ol, 1- (3, 3-diethoxypropyl) cyclohex-1-ol, 1- (2- (1, 3-dioxan-2-yl) ethyl) -4-isopropyl-2-methylcyclohex-1-ol, 1- (2- (1, 3-dioxan-2-yl) ethyl) -4- (tert-butyl) cyclohex-1-ol and 1- (2- (1, 3-dioxan-2-yl) ethyl) -4- (tert-butyl) cyclohex-1-ol.

Another object of the present invention are compounds of formula (V'),

The compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein; each R ¹ And R is ² Each independently represents a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group; r is R ^a And R is ^b Each independently represents C _1-4 Alkyl, or R ^a And R is ^b Taken together represent C _2-6 An alkanediyl group.

Another object of the present invention are compounds of formula (IX),

the compound is in the form of any one of its stereoisomers or mixtures thereof, wherein the dashed line represents a double or triple bond; x represents a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group; each R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently represents a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group; or R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Two groups of (B) together form C _3-8 Cycloalkyl or C _5-8 Cycloalkenyl, the other groups having the same meaning as defined above; with the proviso that 1-vinylcyclohexyl acetate, 1-acetylenyl cyclohexyl acetate, 1-vinylcyclohexyl propionate, 4-methyl-1-vinylcyclohexyl acetate, 2-methyl-1-vinylcyclohexyl acetate, 1-ethynyl-2-methylcyclohexyl acetate, 2-ethyl-1-vinylcyclohexyl acetate, 2-isopropyl-1-vinylcyclohexyl acetate, 2-sec-butyl-1-vinylcyclohexyl acetate, 2-isopropyl-5-methyl-1-vinylcyclohexyl acetate, 2-allyl-1-vinylcyclohexyl acetate, 4-tert-butyl-1-vinylcyclohexyl acetate, 1-vinyldecalin-1-yl acetate and 1-ethynyl decalin-1-yl acetate are excluded.

Detailed Description

It has now surprisingly been found that valuable perfuming ingredients 3- (cyclohex-1-en-1-yl) propanal derivatives of formula (I) can be obtained from novel chemical intermediates as defined below in formula (II), formula (III) and formula (IV). The process of the present invention represents a novel route to the compounds of formula (I) in higher overall yields compared to the processes known from the prior art.

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein each R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently represents a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group; or R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Two groups of (B) together form C _3-8 Cycloalkyl or C _5-8 Cycloalkenyl, other groups having the meaning as described aboveThe same meaning is defined;

For the sake of clarity, by the expression "any one of its stereoisomers or mixtures thereof" or similar expressions, it is meant that the compounds of formula (I) and formula (II) may be pure enantiomers or mixtures of various enantiomers, as understood by a person skilled in the art. In other words, the compounds of formula (I) and formula (II) may have at least one stereocenter, which may have two different stereochemistry (e.g., R or S). The compounds of the formulae (I) and (II) may even be in the form of pure enantiomers or in the form of mixtures of various enantiomers. When the compounds of formula (I) and formula (II) have more than one stereocenter, the compounds of formula (I) and formula (II) may even be in the form of pure diastereomers, or in the form of mixtures of multiple diastereomers. The compounds of formula (I) and formula (II) may be in racemic or non-racemic (scalemic) form. Thus, the compounds of formula (I) and formula (II) may be one stereoisomer or in the form of a composition of matter comprising or consisting of the various stereoisomers.

The term "optionally/optionally" is understood to mean that a certain group to be optionally substituted may or may not be substituted with a certain functional group.

For clarity, by the expression "comprising a hydroformylation and elimination step" it is meant that the hydroformylation reaction and elimination reaction may be carried out in any order. In other words, the process of the invention may comprise a hydroformylation step followed by an elimination step, or the process of the invention may comprise an elimination step followed by a hydroformylation step.

The terms "alkyl" and "alkenyl" are understood to include branched and straight chain alkyl and alkenyl groups. The terms "alkenyl" and "cycloalkenyl" are understood to comprise 1, 2 or 3 olefinic double bonds, preferably 1 or 2 olefinic double bonds. The terms "cycloalkyl" and "cycloalkenyl" are understood to include monocyclic or fused, spiro and/or bridged bicyclic or tricyclic cycloalkyl and cycloalkenyl groups, preferably monocyclic cycloalkyl and cycloalkenyl groups.

For clarity, by the expression "R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Two groups of (B) together form C _3-8 Cycloalkyl or C _5-8 Cycloalkenyl "means that the carbon atom to which the two groups are bonded is included in C _5-8 Cycloalkyl or C _5-8 In cycloalkenyl groups.

According to any embodiment of the invention, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ At least one of the groups may be C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 Alkoxy groups, while the other groups may each independently be hydrogen atoms, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group. In particular, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ At least three groups of (a) may be hydrogen atoms, and the other groups may each be independently hydrogen atoms, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group. In particular, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ The four groups in (a) may be hydrogen atoms, the others may beEach independently is a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group. In particular, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ One, two, three or four groups of (C) _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 Alkoxy groups, the other groups may be hydrogen atoms. Even more particularly, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ One or both groups of (C) _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 Alkoxy groups, the other groups may be hydrogen atoms.

According to any embodiment of the invention, R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently can be a hydrogen atom or C _1-4 Alkyl optionally substituted with hydroxy or C _1-3 An alkoxy group. In particular, R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently can be a hydrogen atom or C _1-3 An alkyl group. In particular, R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently may be a hydrogen atom.

According to a particular embodiment of the invention, R ¹ 、R ² 、R ³ 、R ⁶ And R is ⁷ Can each independently be a hydrogen atom, R ⁴ And R is ⁵ Can be a hydrogen atom or C _1-3 An alkyl group. In particular, R ¹ 、R ² 、R ³ 、R ⁶ And R is ⁷ Each independently can be a hydrogen atom and R ⁴ Can be a hydrogen atom and R ⁵ May be C _1-3 Alkyl, or R ⁴ May be C _1-3 Alkyl and R ⁵ May be a hydrogen atom.

According to any embodiment of the invention, the compound of formula (I) corresponds to formula (I'),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein each R ¹ And R is ² Has the same meaning as defined above;

and the compound of formula (II) corresponds to formula (II'),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein each X, R ¹ And R is ² Has the same meaning as defined above.

According to any embodiment of the invention, R ¹ May be C _1-4 Alkyl or C _2-4 Alkenyl groups. In particular, R ¹ May be methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl or n-butyl. In particular, R ¹ May be methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl or n-butyl. Even more particularly, R ¹ May be methyl.

According to any embodiment of the invention, R ² Can be a hydrogen atom or C _1-3 Alkyl or C _2-3 Alkenyl groups. In particular, R ² May be a hydrogen atom, methyl, ethyl, propyl or isopropyl group. Even more particularly, R ² May be methyl.

According to a particular embodiment of the invention, when R ² When the compound is a hydrogen atom, R is preferable ¹ Is not t-butyl.

According to any of the embodiments of the present invention, X may be a C (O) R group, wherein R may be a hydrogen atom or C _1-4 An alkyl group. In particular, X may be a C (O) R group, wherein R may be C _1-3 An alkyl group. Even more particularly, X may be an acetate group.

According to a particular embodiment of the invention, the process according to the invention comprises a hydroformylation starting from the compound of formula (II), followed by an elimination step. Hydroformylation of compounds of formula (II) provides compounds of formula (III),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein X, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined above.

Hydroformylation may provide compounds of formula (III') as byproducts,

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein X, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined above. Up to 40% by weight of the compound of formula (III') may be formed. In particular, up to 35% by weight of the compound of formula (III') may be formed. In particular, up to 30% by weight of the compound of formula (III') may be formed. In particular, up to 20% by weight of the compound of formula (III') may be formed. In particular, up to 10% by weight of the compound of formula (III') may be formed. In particular, up to 5% by weight of the compound of formula (III') may be formed. Even more particularly, hydroformylation does not provide compounds of formula (III').

For the sake of clarity, by the expression "hydroformylation" or similar expression is meant the normal meaning understood by the person skilled in the art, i.e. the reaction is carried out in the presence of a metal catalyst such as rhodium, cobalt or platinum complexes, preferably rhodium complexes, carbon monoxide, hydrogen and optionally a ligand such as a ligand comprising a phosphorus atom.

According to any embodiment of the invention, the hydroformylation is carried out in the presence of rhodium complexes. Can be used forRhodium complexes useful in the present invention include, but are not limited to Rh (acac) (CO) ₂ 、RhCl ₃ 、Rh ₂ AcO ₄ 、[Rh(OAc)(COD)] ₂ 、Rh ₄ (CO) ₁₂ 、Rh ₆ (CO) ₁₆ 、RhCl(CO)(PPh ₃ ) ₂ 、Rh(C ₂ H ₄ )2(acac)、[Rh(Cl)(COD)] ₂ 、[Rh(Cl)(COE) ₂ ] ₂ 、[Rh(OAc)(CO) ₂ ] ₂ 、Rh(acac)(COD)、HRh(CO)(PPh ₃ ) ₃ 、RhCl(PPh ₃ ) ₃ 、[Rh(NBD) ₂ ]BF ₄ 、[Rh(OMe)(COD)] ₂ And [ Rh (OH) (COD) ]] ₂ Wherein acac represents an acetyl group, ac represents an acetyl group, COD represents a 1, 5-cyclooctadienyl group, COE represents a cyclooctenyl group, and Ph represents a phenyl group. In particular, the rhodium complex may be selected from Rh (acac) (CO) ₂ 、[Rh(OAc)(COD)] ₂ 、RhCl(CO)(PPh ₃ ) ₂ 、Rh(C ₂ H ₄ ) ₂ (acac)、[Rh(Cl)(COD)] ₂ 、[Rh(Cl)(COE) ₂ ] ₂ 、[Rh(OAc)(CO) ₂ ] ₂ 、Rh(acac)(COD)、HRh(CO)(PPh ₃ ) ₃ 、RhCl(PPh ₃ ) ₃ 、[Rh(NBD) ₂ ]BF ₄ 、[Rh(OMe)(COD)] ₂ And [ Rh (OH) (COD) ]] ₂ . Even more particularly, the rhodium complex may be selected from Rh (acac) (CO) ₂ 、Rh(acac)(COD)、HRh(CO)(PPh ₃ ) ₃ 、[Rh(OMe)(COD)] ₂ And [ Rh (OH) (COD) ]] ₂ . The complex may be added to the reaction medium of the process of the present invention in a wide range of concentrations. As non-limiting examples, as the complex concentration values, there may be mentioned values ranging from about 0.0005mol% to about 5mol% with respect to the amount of the substrate, preferably from 0.001mol% to about 5mol% with respect to the amount of the substrate. Preferably, the complex concentration is 0.0025mol% to 2mol%. It goes without saying that the optimal concentration of the complex will depend on the nature of the latter, the nature of the substrate, the nature of the ligand, the reaction temperature and the time required for the reaction, as known to the person skilled in the art.

According to any embodiment of the invention, the hydroformylation is carried out in the presence of a monodentate or bidentate phosphorus ligand. In particular the number of the elements to be processed,the phosphorus ligand may be a bidentate phosphorus ligand. In particular, the monodentate or bidentate phosphorus ligand is not selected from [1- [2- (12, 14-dioxa-13-phosphapentacyclic [13.8.0.0 ] ^2,11 .0 ^3,8 .0 ^18,23 ]Ditridecan-1 (15), 2 (11), 3,5,7,9,16,18,20,22-decaen-13-yloxy) naphthalen-1-yl]Naphthalen-2-yl]-diphenylphosphine or-diazaphospholane (diazaphospholane) ligands.

According to any of the embodiments of the invention, the hydroformylation may be carried out in the formula PR ⁸ ₃ In the presence of monodentate phosphorus ligands, wherein R ⁸ Is C ₁ -C ₁₂ Groups, e.g. optionally substituted straight-chain, branched or cyclic alkyl, alkoxy or aryloxy, substituted or unsubstituted phenyl, biphenyl, 2-furyl, naphthyl or dinaphthyl, or two R groups ⁸ The radicals together forming a phosphatrioxaadamantane, another R ⁸ The radicals have the same meanings as above. More particularly, R ⁸ May represent a substituted or unsubstituted phenyl, biphenyl, naphthyl or dinaphthyl group. Possible substituents are the following radicals R ⁹ Those listed. Preferably, the monodentate phosphorus ligand is triphenylphosphine.

According to any of the above embodiments, the hydroformylation may be carried out in the presence of a bidentate phosphorus ligand of the formula,

(R ^g ) ₂ P-Q-p(R ^g ) ₂ (A)

wherein each R is ⁹ Independently represents optionally substituted C _6-10 An aromatic group or an optionally substituted cyclohexyl group, or two R's bonded to the same P atom ⁹ Taken together represent an optionally substituted 1,1 '-biphenyl-2, 2' -dioxy group; and is also provided with

Q represents a group of the formula:

-a)

wherein q is 0 or 1, each T independently represents an oxygen atom or CH ₂ Groups, each R ¹⁰ Each independently represents a hydrogen atom orC _1-8 Alkyl, and Z represents an oxygen or sulfur atom or C (R ¹¹ ) ₂ 、Si(R ¹² ) ₂ Or NR (NR) ¹¹ A group, wherein R is ¹¹ Is a hydrogen atom or R ¹² A group R ¹² Represents C _1-4 A linear or branched alkyl group, preferably methyl; or alternatively

-b)

In the form of any one of its enantiomers, wherein q is 0 or 1, r is 0 or 1, each T independently represents an oxygen atom or CH ₂ A group R ¹³ Each independently represents a hydrogen atom or C optionally substituted with one to three halogen atoms or alkoxy groups _1-4 An alkyl group;

-c)

in the form of any one of its enantiomers, wherein R ¹³ Having the same definition as above;

the wavy line indicates the bonding position between the Q group and the rest of compound (a).

According to any of the embodiments described above, Q may be a group of formula (i) or formula (ii).

According to any one of the embodiments above, each R ⁹ May be optionally substituted C _6-10 An aromatic group or an optionally substituted cyclohexyl group.

According to any of the embodiments described above, an "aromatic group or ring" refers to a phenyl or naphthyl group, in particular a phenyl group.

According to any one of the embodiments above, each R ⁹ Can be phenyl, cyclohexyl, 3, 5-dimethyl-phenyl, 3, 5-di (CF) ₃ ) -phenyl, 3, 5-dimethyl-4-methoxy-phenyl.

According to any of the above embodiments, R ¹⁰ May be a hydrogen atom.

According to any of the above embodiments, Z may be CMe ₂ 、SiMe ₂ An NH or NMe group. In particular, Z may be CMe ₂ A group.

According to any of the above embodiments, R ⁹ Non-limiting examples of possible substituents of (a) are one, two, three or four selected from halogen atoms or C _1-10 Alkoxy, alkyl, alkenyl, pyridyl or perhalogenated hydrocarbon groups. The two substituents may be taken together to form C _4-8 Cycloalkyl groups. The expression "perhalogenated hydrocarbon" has the meaning usual in the art, for example such a group, for example CF ₃ . In particular, the substituents are one or two halogen atoms, e.g. F or Cl, or C _1-4 Alkoxy or alkyl, or CF ₃ A group.

According to any of the above embodiments, the R ⁹ May be unsubstituted.

According to any of the embodiments described above, the ligand of formula (a) may be in racemic or optically active form.

Non-limiting examples of bidentate phosphorus ligands may include 2,2 '-bis ((di (1H-pyrrol-1-yl) phosphino) oxy) -1,1' -binaphthyl, 1'- ((naphthalene-2-oxy) phosphinodiyl) bis (1H-pyrrole), 2' -bis ((di (1H-pyrrol-1-yl) phosphino) oxy) -1,1 '-biphenyl, (9, 9-dimethyl-9H-xanthen-4, 5-diyl) bis (diphenylphosphine), 2' -bis ((di (1H-pyrrol-1-yl) phosphino) oxy) -5,5', 6', 7',8,8' -octahydro-1, 1 '-binaphthyl, 1', 1%, 1'- ((2, 7-di-tert-butyl-9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (oxy)) bis (phosphinotrigyl)) tetrakis (1H-pyrrole), 6' - [ (3, 3 '-di-tert-butyl-5, 5' -dimethoxy-1, 1 '-biphenyl-2, 2' -diyl) bis (oxy) ] bis (dibenzo [ d), f ] [1,3,2] dioxaphosphepin), (oxybis-2, 1-phenylene) bis (diphenylphosphine), 2 '-bis (diphenylphosphinomethyl) -1,1' -biphenyl, 4, 6-bis (diphenylphosphino) -10H-phenoxazine, 2- ((3, 3' -di-tert-butyl-2 ' - ((4, 8-di-tert-butyl-2, 10-dimethoxydibenzo [ d, f ] [1,3,2] dioxaphosphepin-6-yl) oxy) -5,5' -dimethoxy- [1,1' -biphenyl ] -2-yl) oxy) -4H-naphtho [2,3-d ] [1,3,2] dioxaphosphepin-4-one, 2- ((3, 3' -di-tert-butyl-2 ' - ((4, 8-di-tert-butyl-2, 10-dimethoxydibenzo [ d, f ] [1,3,2] dioxaphosphepin-6-yl) oxy) -5,5' -dimethoxy- [1,1' -biphenyl ] -2-yl) oxy) -8-methyl-4H-benzo [ d ] [1,3,2] dioxa-nyl ] ((S-4, 3-di-tert-butyl-2 ' - ((4, 8-dimethoxy-dibenzo [ d, f ] [1,3,2] dioxaphosphepin-6-yl) oxy) -5,5' -dimethoxy- [1,1' -biphenyl ] -2-yl) oxy ] ((S-di-tert-butyl-4-phenyl) - (-) -9-dimethyl-9-di-tert-butyl-4-phenyl) - ((S-9-dimethyl) -9-dimethyl-9-p-1, 9-dimethyl-1-S-4-dimethyl-1-4-dimethyl-1-diphenyl-1-yl-1-p-yl) of-1 8-methyl-2- ((3, 3', 5' -tetra-tert-butyl-2 ' - ((2, 4,8, 10-tetra-tert-butyldibenzo [ d, f ] [1,3,2] dioxaphosphepin-6-yl) oxy) - [1,1' -biphenyl ] -2-yl) oxy) -4H-benzo [ d ] [1,3,2] dioxaphosphepin-4-one, 2- ((3, 3' -di-tert-butyl-2 ' - ((4, 8-di-tert-butyl-2, 10-dimethoxydibenzo [ d, f ] [1,3,2] dioxaphosphepin-6-yl) oxy) -5,5' -dimethoxy- [1,1' -biphenyl ] -2-yl) oxy) -8-isopropyl-5-methyl-4H-benzo [ d ] [1,3,2] dioxaphosphepin-4-one, (S, 1' S) - (+) (9, 9-dimethoxy) (4-di-phenyl) (9-di-tert-butyl-2-methoxy) (4, 9-dimethyl) (4-2-yl) oxy) - (-8-isopropyl-5-methyl-4H-benzo [ d ] (-1, 3, 2-methyl) dioxa-2-yl) oxy) (1S, 1 'S) - (+) - (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis ((2-methylphenyl) (phenyl) phosphine), (1S, 1' S) - (-) - (9, 9-dimethyl-9H-xanthen-4, 5-diyl) bis (naphthalen-2-yl (phenyl) phosphine), (1S, 1 'S) - (-) - (9, 9-dimethyl-9H-xanthen-4, 5-diyl) bis ((4-methoxyphenyl) (phenyl) phosphine), (1S, 1' S) - (-) - (2, 7-di-tert-butyl-9, 9-dimethyl-9H-xanthen-4, 5-diyl) bis ((2-naphthyl) (phenyl) phosphine), (1S, 1 'S) - (-) - (9, 9-dimethyl-9H-xanthen-4, 5-diyl) bis (naphthalen-1-yl (phenyl) phosphine), (1S, 1' S) - (+) (2, 7-di-tert-butyl-9, 9-dimethyl-9H-xanthen-4, 5-diyl) phosphine, 3-yl (phenyl) phosphine), (1S, 1' S) - (+) - (2, 7-di-tert-butyl-9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis ((2-isopropylphenyl) (phenyl) phosphine) or (1S, 1' S) - (-) - (2, 7-di-tert-butyl-9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis ((dibenzo [ b, d ] -furan-4-yl) (phenyl) phosphine), (2, 7-di-tert-butyl-9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis ((4-methoxyphenyl) (phenyl) phosphine), (4, 4', 6' -tetramethoxybiphenyl-2, 2' -diyl) bis { bis [3, 5-bis (trifluoromethyl) phenyl ] phosphine }.

In particular, the ligand is a bidentate phosphorus ligand, which may be selected from: (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine), 1',1", 1' - ((2, 7-di-tert-butyl-9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (oxy)) bis (phosphinotrigyl)) tetrakis (1H-pyrrole), 6' - [ (3, 3' -di-tert-butyl-5, 5' -dimethoxy-1, 1' -biphenyl-2, 2' -diyl) bis (oxy) ] bis (dibenzo [ d), f ] [1,3,2] dioxaphosphepin), (oxydi-2, 1-phenylene) bis (diphenylphosphine), 2' -bis (diphenylphosphinomethyl) -1,1' -biphenyl, 4, 6-bis (diphenylphosphino) -10H-phenoxazine, 2- ((3, 3' -di-tert-butyl-2 ' - ((4, 8-di-tert-butyl-2, 10-dimethoxydibenzo [ d, f ] [1,3,2] dioxaphosphepin-6-yl) oxy) -5,5' -dimethoxy- [1,1' -biphenyl ] -2-yl) oxy) -4H-naphtho [2,3-d ] [1,3,2] dioxaphosphepin-4-one, 2- ((3, 3' -di-tert-butyl-2 ' - ((4, 8-di-tert-butyl-2, 10-dimethoxydibenzo [ d), f ] [1,3,2] dioxaphosphepin-6-yl) oxy) -5,5 '-dimethoxy- [1,1' -biphenyl ] -2-yl) oxy) -8-methyl-4H-benzo [ d ] [1,3,2] dioxaphosphepin-4-one, (1S, 1 'S) - (-) - (2, 7-di-tert-butyl-9, 9-dimethyl-9H-xanthen-4, 5-diyl) bis ((1-naphthyl) (phenyl) phosphine) or (1S, 1' S) - (-) - (2, 7-di-tert-butyl-9, 9-dimethyl-9H-xanthen-4, 5-diyl) bis ((4-methylphenyl) (phenyl) phosphine).

The phosphorus ligand may be added to the reaction medium of the process of the present invention in a wide range of concentrations. As non-limiting examples, as phosphorus ligand concentration values, values in the range of about 0.001mol% to about 50mol% relative to the amount of substrate, preferably 0.005mol% to about 50mol% relative to the amount of substrate, can be cited. Preferably from about 0.005mol% to about 15mol% relative to the amount of substrate. As known to those skilled in the art, the optimal concentration of the phosphorus ligand will depend on the nature of the latter, the nature of the substrate, the nature of the metal complex, the reaction temperature and the time required for the reaction.

According to any of the embodiments described above, carbon monoxide and hydrogen may be generated in situ by methods known to those skilled in the art, for example from methyl formate, formic acid or formaldehyde. CO/H ₂ The gas volume ratio is 2/1 to 1/5, preferably 1/1 to 1/5, or preferably 2/1 to 1/2, preferably 1.5/1 to 1/1.5, more preferably the ratio is 1/1.

The reaction may be carried out in the presence or absence of a solvent. Any solvent stream in such reaction types may be used for the purposes of the present invention when a solvent is needed or used for practical reasons. Non-limiting examples include C _6-12 Aromatic solvents such as toluene, 1, 3-diisopropylbenzene, cumene or pseudo-cumene or mixtures thereof, alcoholic solvents such as methanol, ethanol, 2-methylbutan-2-ol or mixtures thereof, hydrocarbon solvents such as cyclohexane, heptane or mixtures thereof, ester solvents such as n-butyl acetate, isopropyl acetate, ethyl acetate, or ether solvents such as methyltetrahydrofuran, tetrahydrofuran or mixtures thereof. The choice of solvent depends on the nature of the substrate and/or the catalyst and the person skilled in the art is well able to choose the most suitable solvent in each case to optimise the reaction.

The hydroformylation reaction may be carried out at a temperature in the range 50 ℃ to 150 ℃, more preferably 80 ℃ to 130 ℃, or even in the range 90 ℃ to 110 ℃. Of course, the skilled person can also choose the preferred temperature depending on the melting and boiling points of the starting and final products and the time required for the reaction or conversion.

The hydroformylation may be at a CO/H of from 1 bar to 50 bar, preferably from 10 bar to 50 bar, more preferably from 25 bar to 35 bar ₂ Under pressure. Of course, the person skilled in the art is able to adjust the pressure according to the catalyst loading and the dilution of the substrate in the solvent.

According to any embodiment of the present invention, the aldehyde group of the compound of formula (III) may be protected prior to the elimination step, or the elimination step may be performed directly on the compound of formula (III) to provide the compound of formula (I). When the elimination step is carried out on the compound of formula (III), the elimination is carried out under acidic conditions or under pyrolysis. The acid is selected from pTsOH, msOH, tfOH, H ₂ SO ₄ 、H ₃ PO ₄ 、KHSO ₄ 、NaHSO ₄ Oxalic acid, formic acid, BF ₃ .Et ₂ O、BF ₃ AcOH, alox acid (Axsorb A2-5, al ₂ O ₃ 504C)、Amberlyst 15、SiO ₂ TFA, wayphos, polyphosphoric acid, zeolite (CBV 780, zeoli sold by Zeolist as CBV 21A, zeolist)CP814E sold by st), boric acid, al ₂ (SO ₄ ) ₃ CSA, pyridinium p-toluenesulfonate, znBr ₂ K10-S300 (bentonite) sold by Clariant, F24X (bentonite) sold by Clariant, sasol

40HPV、HCl、HBr、Zn(SO ₄ ) ₂ 、ZnCl ₂ 、MgI ₂ And mixtures thereof. Pyrolysis may be carried out at a temperature in the range of 300 ℃ to 600 ℃.

The elimination reaction of the aldehyde substrate may be performed in the presence or absence of a solvent. Any solvent stream in such reaction types may be used for the purposes of the present invention when a solvent is needed or used for practical reasons. Non-limiting examples include C _6-12 Aromatic solvents such as toluene, xylene, 1, 3-diisopropylbenzene, cumene or pseudo-cumene or mixtures thereof, chlorinated solvents such as methylene chloride, dichloroethane or mixtures thereof, hydrocarbon solvents such as cyclohexane or heptane. The choice of solvent depends on the nature of the substrate and/or the catalyst and the person skilled in the art is well able to choose the most suitable solvent in each case to optimise the reaction.

The step of eliminating the aldehyde substrate under acidic conditions may be performed at a temperature in the range of 20 ℃ to 110 ℃. Of course, the skilled person can also choose the preferred temperature depending on the melting and boiling points of the starting and final products and the time required for the reaction or conversion.

According to any embodiment of the invention, the method comprises the steps of:

a) Hydroformylation of the compounds of formula (II) to give compounds of formula (III),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein X, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined above

b) Protecting the aldehyde group of the compound of formula (III) obtained in step a) in the form of an acetal of formula (IV),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein X, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined above and R ^a And R is ^b Each independently represents C _1-4 Alkyl, or R ^a And R is ^b Taken together represent C _2-6 An alkanediyl group;

c) Elimination of the OX group of the compound of formula (IV) followed by isomerization to form the compound of formula (V),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ^a And R is ^b Has the same meaning as defined above; and

d) Deprotection of the acetal groups to give compounds of formula (I).

The term "alkanediyl" is understood to include both branched and straight chain alkanediyl.

According to any embodiment of the invention, R ^a And R is ^b Can be taken together to represent C _2-6 An alkanediyl group. In particular, R ^a And R is ^b Can be taken together to represent C _2-4 An alkanediyl group. Even more particularly, R ^a And R is ^b Taken together represent (CH) ₂ ) _n A group, wherein n may be 2 or 3; preferably n may be 2.

According toIn any of the embodiments of the invention, the protection of the aldehyde group of the compound of formula (III) obtained in step a) in the form of an acetal of formula (IV) can be carried out under normal conditions known to the person skilled in the art, i.e. with orthoformic acid C _1-4 Trialkyl esters, C _1-4 Alcohol and C _2-6 Diols and in the presence of acids. Specific and non-limiting examples of acids may be selected from H ₂ SO ₄ 、KHSO ₄ 、NaHSO ₄ 、H ₃ PO ₄ 、NaHSO ₄ Amberlyst 15, pTsOH, msOH, tfOH, CSA, oxalic acid, formic acid, TFA, BF ₃ .Et ₂ O、BF ₃ .AcOH、HBF ₄ 、wayphos、SiO ₂ Pyridinium p-toluenesulfonate, zeolite and Al ₂ (SO ₄ ) ₃ F24X (bentonite), boric acid, and mixtures thereof.

Orthoformic acid C _1-4 Trialkyl esters, C _1-4 Alcohol and C _2-6 Specific and non-limiting examples of diols may be selected from trimethyl orthoformate, triethyl orthoformate, methanol, ethanol, ethylene glycol, 1, 2-butanediol, 2, 3-dimethyl-3-hydroxy-2-butanol, diglycerol, trans-1, 2-cyclohexanediol, neopentyl glycol, 1, 3-propanediol, 2-methyl-2-propyl-1, 3-propanediol, 1, 2-propanediol, 2-methyl-1, 2-propanediol, 2-dimethyl-1, 3-propanediol. In particular, C can be used _2-6 The formation of acetals is carried out by diols, in particular ethylene glycol.

Orthoformic acid C _1-4 Trialkyl esters, C _1-4 Alcohols or C _2-6 The diol may be added to the reaction medium of the process of the present invention in a wide range of concentrations. As a non-limiting example, as orthoformic acid C _1-4 Trialkyl esters or C _2-5 The diol concentration value may be exemplified by values ranging from about 1 to about 2 equivalents relative to the amount of substrate. As a non-limiting example, as C _1-4 The alcohol concentration value may be exemplified by values ranging from about 2 to about 4 equivalents relative to the amount of substrate. As known to those skilled in the art, orthoformic acid C _1-4 Trialkyl esters, C _1-4 Alcohols or C _2-6 The optimum concentration of glycol will depend on the nature of the latter, the nature of the substrate, the reaction temperature and the time required for the reaction.

The acid in acetal form used in the step of protecting the aldehyde group of formula (III) can be added to the reaction medium of the process of the present invention in a wide range of concentrations. As non-limiting examples, as the acid concentration value, a value ranging from about 0.1 to about 5mol% with respect to the amount of the substrate can be cited. As known to those skilled in the art, the optimal concentration of the acid will depend on the nature of the latter, the nature of the substrate, the reaction temperature and the time required for the reaction.

According to any of the embodiments of the present invention, the process of forming the compound of formula (IV) of the present invention is carried out at a temperature of 25 ℃ to 120 ℃. In particular, the temperature is in the range of 50 ℃ to 110 ℃. Of course, the person skilled in the art is also able to choose the preferred temperature depending on the melting and boiling points of the starting and final products and the time required for the reaction or conversion.

The acetal formation can be carried out in the presence or absence of a solvent. Any solvent stream in such reaction types may be used for the purposes of the present invention when a solvent is needed or used for practical reasons. Non-limiting examples include C _6-12 Aromatic solvents such as xylene, toluene, 1, 3-diisopropylbenzene, cumene or pseudo-cumene or mixtures thereof, hydrocarbon solvents such as cyclohexane, heptane or mixtures thereof. The choice of solvent depends on the nature of the substrate and/or the catalyst and the person skilled in the art is well able to choose the most suitable solvent in each case to optimise the reaction.

According to any embodiment of the present invention, the elimination of the OX group of the compound of formula (IV) followed by isomerization to form the compound of formula (V) may be carried out under normal conditions known to the person skilled in the art, i.e. pyrolysis and then isomerization, for example under acidic conditions or in the presence of a metal catalyst in elemental form or supported such as rhodium, ruthenium, iridium, platinum or palladium complexes. Elimination of possible exo isomers (having double bonds in the alkyl chain), endo isomers (having double bonds in the ring-the desired compound) or mixtures thereof. Isomerization allows the conversion of exo isomers to endo isomers. In particular, the elimination and isomerization may be a one-pot process carried out in the presence of an acid. The acid may be a lewis acid or a Bronsted (Bronsted) acid. Of acids Specific and non-limiting examples may be selected from p-TsOH, msOH, tfOH, H ₂ SO ₄ 、H ₃ PO ₄ 、KHSO ₄ 、NaHSO ₄ Oxalic acid, formic acid, BF ₃ .Et ₂ O、BF ₃ AcOH, alox acid (Axsorb A2-5, al ₂ O ₃ 504C)、Amberlyst 15、SiO ₂ TFA, wayphos, polyphosphoric acid, zeolite (CBV 780 sold by Zeolist as CBV 21A, zeolist, CP814E sold by Zeolist), boric acid, al ₂ (SO ₄ ) ₃ CSA, pyridinium p-toluenesulfonate, znBr ₂ K10-S300 (bentonite) sold by Clariant, F24X (bentonite) sold by Clariant, sasol

40HPV、HCl、HBr、Zn(SO ₄ ) ₂ 、ZnCl ₂ 、MgI ₂ And mixtures thereof.

The acid used in the one-pot elimination/isomerization reaction may be added to the reaction medium of the process of the present invention in a wide range of concentrations. As non-limiting examples, as acid concentration values, values in the range of about 1mol% to about 20mol% with respect to the amount of substrate, preferably 2mol% to about 10mol% with respect to the amount of substrate, preferably about 3mol% to about 6mol% with respect to the amount of substrate can be cited. As known to those skilled in the art, the optimal concentration of acid will depend on the nature of the latter, the nature of the substrate, the reaction temperature and the time required for the reaction.

According to any of the embodiments of the present invention, the process of forming the compound of formula (V) of the present invention is carried out at a temperature ranging from room temperature to 160 ℃. In particular, the temperature is in the range of 90 ℃ to 140 ℃. Of course, the person skilled in the art is also able to choose the preferred temperature depending on the melting and boiling points of the starting and final products and the time required for the reaction or conversion.

The one-pot elimination/isomerization reaction may be performed in the presence or absence of a solvent. Any solvent stream in such reaction types may be used for the purposes of the present invention when a solvent is needed or used for practical reasons. Non-limiting examples include C _6-12 Aromatic solvents such as xylene, toluene, 1, 3-diisopropylbenzene, cumene or pseudo-cumene or mixtures thereof, hydrocarbon solvents such as cyclohexane, heptane or mixtures thereof, ester or ether solvents such as butyl acetate, diisopropyl ether, dioxane, dimethoxyethane or mixtures thereof. The choice of solvent depends on the nature of the substrate and/or the catalyst and the person skilled in the art is well able to choose the most suitable solvent in each case to optimise the reaction.

According to a particular embodiment, the protection, elimination and isomerisation reactions may be carried out in one pot.

According to any of the embodiments of the present invention, the deprotection of the acetal groups to obtain the compound of formula (I) can be carried out under normal conditions known to the person skilled in the art, i.e. using a large molar excess of carboxylic acid in water. Specific and non-limiting examples of carboxylic acids may be selected from acetic acid, propionic acid, citric acid, formic acid, TFA, oxalic acid, or mixtures thereof.

The carboxylic acid used for deprotection can be added to the reaction medium of the process of the present invention in a wide range of concentrations. As non-limiting examples, as acid concentration values, there may be cited values ranging from about 5 to about 20 equivalents relative to the amount of substrate, preferably from 5 to about 10 equivalents relative to the amount of substrate. As known to those skilled in the art, the concentration of the acid will depend on the nature of the latter, the nature of the substrate, the reaction temperature and the time required for the reaction.

According to any of the embodiments of the present invention, the deprotection to form the compound of formula (I) may be carried out at a temperature of 40 ℃ to 120 ℃. In particular, the temperature is in the range of 70 ℃ to 90 ℃. Of course, the person skilled in the art is also able to choose the preferred temperature depending on the melting and boiling points of the starting and final products and the time required for the reaction or conversion.

According to any embodiment of the present invention, deprotection may be carried out in the presence or absence of a solvent to form a compound of formula (I). Any solvent stream in such reaction types may be used for the purposes of the present invention when a solvent is needed or used for practical reasons. Non-limiting examples include C _6-12 Aromatic solvents such as toluene,Xylene, 1, 3-diisopropylbenzene, cumene or pseudo-cumene or mixtures thereof, an alcoholic solvent such as methanol, ethanol, 2-methylbutan-2-ol or mixtures thereof, a hydrocarbon solvent such as cyclohexane, heptane or mixtures thereof, an ester solvent such as n-butyl acetate, isopropyl acetate, ethyl acetate, or an ether solvent such as methyltetrahydrofuran, tetrahydrofuran or mixtures thereof. The choice of solvent depends on the nature of the substrate and the carboxylic acid derivative and the person skilled in the art is well able to choose the most convenient solvent in each case to optimise the reaction.

According to a particular embodiment, the protection, elimination, isomerization and deprotection reactions may be carried out in one pot.

According to a particular embodiment of the invention, the process according to the invention comprises an elimination step starting from the compound of formula (II), followed by hydroformylation. The method of the invention comprises the following steps:

a) Elimination of the OX 'group of the compound of formula (II'),

the compound is in the form of any one stereoisomer or a mixture thereof, wherein X' is a hydrogen atom, C _1-3 Alkyl, C _2-3 Alkenyl, benzyl or a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group; wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ Has the same meaning as defined;

to obtain a compound of formula (VI),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined above; and

b) Hydroformylation of compounds of formula (VI) to give compounds of formula (I).

The conditions for elimination and hydroformylation are similar to those described above. When X ' is a hydrogen atom, the elimination of the OX ' group of the compound of formula (II ') can also be carried out in the presence of phosphorus oxychloride and an amine such as pyridine or in the presence of methanesulfonyl chloride and triethylamine.

The process of the invention for preparing the compounds of the formula (I) can be carried out batchwise (batchwise) and/or continuously. In particular, the elimination step may be carried out under continuous conditions.

The compounds of formula (II), formula (III), formula (IV) and formula (V') are novel compounds in general and have many advantages as explained above and shown in the examples.

It is therefore a further object of the present invention to provide compounds of formula (III),

Another object of the present invention are compounds of formula (IV'),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein X' is a hydrogen atom, C _1-3 Alkyl, C _2-3 Alkenyl, benzyl or a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group; each R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently represents a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group; or R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Two groups of (B) together form C _3-8 Cycloalkyl or C _5-8 Cycloalkenyl, the other groups having the same meaning as defined above; r is R ^a And R is ^b Each independently represents C _1-4 Alkyl, or R ^a And R is ^b Taken together represent C _2-6 An alkanediyl group; with the proviso that 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4-isobutyl-2-methylcyclohex-1-ol, 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4- (tert-butyl) -2-methylcyclohex-1-ol, 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4-isopropyl-2-methylcyclohex-1-ol, 1- (3, 3-diethoxypropyl) cyclohex-1-ol, 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4- (tert-butyl) cyclohex-1-ol and 1- (2- (1, 3-dioxan-2-yl) ethyl) -4- (tert-butyl) cyclohex-1-ol are excluded. In particular, the compounds of formula (IV') correspond to formula (IV),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and Wherein X represents a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group; each R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently represents a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group; or R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Two groups of (B) together form C _3-8 Cycloalkyl or C _5-8 Cycloalkenyl, the other groups having the same meaning as defined above; r is R ^a And R is ^b Each independently represents C _1-4 Alkyl, or R ^a And R is ^b Taken together represent C _2-6 An alkanediyl group.

Another object of the present invention are compounds of formula (V'),

Another object of the present invention is a process for preparing a compound of formula (II),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein X represents a C (O) R group or Si (R') ₃ A group in whichR is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group; each R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently represents a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group; or R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Two groups of (B) together form C _3-8 Cycloalkyl or C _5-8 Cycloalkenyl, the other groups having the same meaning as defined above;

comprising the step of reducing a compound of formula (VII),

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the compound is in the form of any one of its stereoisomers or mixtures thereof, wherein X 'is a hydrogen atom, a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group; wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined.

According to a particular embodiment, the method of the invention comprises the following steps:

a) Reducing a compound of formula (VII ') to a compound of formula (II'),

the compound is in the form of any one of its stereoisomers or mixtures thereof, wherein R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined above;

the compound is in the form of any one of its stereoisomers or mixtures thereof, wherein R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined above; and

b) Protecting the compound (II' ") to give the compound of formula (II).

According to another particular embodiment, the method of the invention comprises the following steps:

a) Protecting the compound of formula (VII ') into a compound of formula (VII'),

the compound is in the form of any one of its stereoisomers or mixtures thereof, wherein R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined above; and X represents a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group; and

b) The compound (VII') is reduced to give the compound of formula (II).

For the sake of clarity, by the expression "wherein the dashed lines represent double or triple bonds" or the like, it is meant that the normal meaning as understood by the person skilled in the art is that the whole bonds (solid and dashed) between the carbon atoms connected by said dashed lines are carbon-carbon double bonds or carbon-carbon triple bonds.

According to any embodiment of the invention, the reduction is hydrogenation. In particular, the hydrogenation can be carried out in the presence of heterogeneous catalysts such as palladium in elemental metallic form. In particular, the palladium may be supported on a support material. For the sake of clarity, by carrier material is meant a material in which such a metal can be deposited and which is inert to the hydrogen source and the substrate. Supported palladium is a known compound and is commercially available. The person skilled in the art is able to choose the way in which it is deposited on the support, such as the proportion of metal on the support material, the form of the support (powder, granules, pellets, extrudates, foam … …) and the surface area. In particular, the heterogeneous catalyst may be a Lindlar catalyst, palladium carbon powder (under the trademark Nanoselect ^TM LF 100 is known from: BASF) or palladium titanium silicate powder (under the trademark Nanoselect ^TM LF 200 is known from: BASF). The hydrogenation may be carried out under normal conditions known to those skilled in the art, which will be able to set the optimum conditions for converting the compound of formula (VII ') into the compound of formula (II' ") or for converting the compound of formula (VII") into the compound of formula (II).

The reduction may be carried out in the presence of an additive such as 3, 6-dithio-1, 8-octanediol.

Palladium may be added to the reaction medium of the process of the present invention in a wide range of concentrations. As non-limiting examples, as palladium concentration values, values in the range of about 0.005mol% to about 10mol% with respect to the amount of the substrate, preferably 0.01mol% to about 1mol% with respect to the amount of the substrate, preferably about 0.01mol% to about 0.2mol% with respect to the amount of the substrate, preferably about 0.03mol% to about 0.1mol% with respect to the amount of the substrate can be cited. As known to those skilled in the art, the optimal concentration of palladium will depend on the nature of the latter, the nature of the substrate, the nature of the catalyst, the reaction temperature, and the time required for the reaction.

Additives such as 3, 6-dithio-1, 8-octanediol may be added to the reaction medium of the process of the present invention in a wide range of concentrations. As non-limiting examples, as additive concentration values, values of about 1 to 50mol.% with respect to the amount of palladium, preferably 5 to 40mol.% with respect to the amount of palladium, preferably 5 to 25mol.% with respect to the amount of palladium, may be cited. As known to those skilled in the art, the optimum concentration of the additive will depend on the nature of the latter, the nature of the substrate, the nature of the catalyst, the reaction temperature and the time required for the reaction.

Hydrogenation can be carried out at 10 ⁴ Pa to 3x10 ⁵ H of Pa (0.1 to 3 bar) ₂ Under pressure. In particular, the hydrogenation can be carried out at 3X10 ⁴ Pa to 10 ⁵ H of Pa (0.3 to 1 bar) ₂ Under pressure. Also, the person skilled in the art is well able to adjust the pressure according to the catalyst loading.

According to any of the embodiments of the present invention, the hydrogenation is carried out at a temperature of from 10 ℃ to 50 ℃. In particular, the temperature is in the range of 20 ℃ to 35 ℃. Of course, the person skilled in the art is also able to choose the preferred temperature depending on the melting and boiling points of the starting and final products and the time required for the reaction or conversion.

The hydrogenation may be carried out in the presence or absence of a solvent. Any solvent stream in such reaction types may be used for the purposes of the present invention when a solvent is needed or used for practical reasons. Non-limiting examples include C _6-12 Aromatic solvents such as xylene, toluene, 1, 3-diisopropylbenzene, cumene or pseudo-cumene or mixtures thereof, hydrocarbon solvents such as cyclohexane, heptane or mixtures thereof, alcohol solvents such as methanol, ethanol, 2-methylbutan-2-ol or mixtures thereof, ketone solvents such as acetone, acetophenone, butanone, cyclopentanone or mixtures thereof, ether solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, methyltetrahydrofuran or mixtures thereof, ester solvents such as ethyl acetate, isopropyl acetate or mixtures thereof. The choice of solvent depends on the nature of the substrate and/or the catalyst and the person skilled in the art is well able to choose the most suitable solvent in each case to optimise the reaction.

According to any embodiment of the invention, the protecting stepThe procedure may depend on the nature of the X group. It is clear to the person skilled in the art that X is Si (R') in the form of an ester, X is C (O) R, or in the form of a silane ₃ The groups protect the conditions to which the alcohol is applied. Typical conditions can be found in a large number of documents in the field of organic chemistry, such as Protective Groups in Organic Synthesis,3rd Edition.Theodora W.Green (The Rowland Institute for Science) and Peter g.m. wuts (Pharmacia and Upjohn Company). John Wiley&Sons,Inc.,New York,NY.1999.xxi+779pp.15.5×23cm.ISBN 0-471-16019-9。

According to any of the embodiments of the present invention, the compound of formula (VII') may be prepared by ethynylation of a ketone of formula (VIII),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein each R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently represents a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group; or R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Two groups of (B) together form C _3-8 Cycloalkyl or C _5-8 Cycloalkenyl, the other groups have the same meaning as defined above. The conditions used for obtaining compound (VII') starting from compound (VIII) are well known to those skilled in the art. Such reactions have been widely reported in the prior art. Thus, the person skilled in the art will be able to set the optimum conditions for converting the compound of formula (VIII) into the compound of formula (VII'). As non-limiting examples, the reaction may be carried out under conditions reported in Angewandte Chemie, international Edition,2020,1666-1673, WO2009126584 or WO 2014056851.

Another object of the present invention are compounds of formula (IX),

Disclosed herein is a process for preparing a compound of formula (X),

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the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein each R ² ' stands for C _1-4 An alkyl group;

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein R ² 'has the same meaning as defined in formula (I), and X represents a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group.

The process for preparing the compound (X) is carried out according to the same embodiment as the process for preparing the compound of formula (I).

Typical ways of carrying out the method of the invention are reported in the examples below.

Examples

The invention will now be described in more detail by the following examples, in which the abbreviations have the usual meaning in the art, the temperatures being indicated in degrees celsius (°c). The preparation of the precatalyst and ligand solution was carried out under an inert atmosphere (argon) using standard Schlenk techniques. The solvent was dried by conventional procedure and distilled under argon atmosphere. NMR spectra were recorded at 20 ℃ on Bruker AV 300, AV 400 or AV 500MHz spectrometers. Chemical shift relative to solvent signal (chloroform, delta _H ＝7.26ppm，δ _C =77.0 ppm) is reported in ppm. By recording ¹ H、 ¹ H-COSY、-NOESY、 ¹³ C、 ¹ H-HSQC and-HMBC experiments to ensure signal distribution. Gas chromatography was performed on an Agilent 7890A series equipped with HP5 column (30m x 0.25mm ID,0.25 μm membrane) and tetradecane was used as internal standard.

Example 1

Preparation of 4, 4-dimethyl-1-vinylcyclohexyl acetate by hydrogenation followed by esterification

a) Step 1: preparation of 1-vinyl-4, 4-dimethylcyclohexanol

1-ethynyl-4, 4-dimethylcyclohexanol (CAS No. 68483-62-5), acetone (100 wt.%), lindlar catalyst (0.5 wt.%, 0.036mol.% Pd) and 3, 6-dithio-1, 8-octanediol (Lindlar catalyst poison, CAS No. 5244-34-8) (0.005 wt.%, 12mol.% relative to Pd) were charged together into a 100mL or 1L autoclave equipped with a mechanical stirring device, pressure and internal temperature sensors, and a heating/cooling system for internal temperature regulation. The sealed autoclave was then purged with nitrogen (3 times 5 bar) with stirring, then stirred at 25 ℃ and 1 bar nitrogen pressure for 30 minutes. After this time, the autoclave was purged with hydrogen (3 times 1 bar) with stirring, and then pressurized to a hydrogen pressure of 1 bar by a hydrogen tank equipped with an outlet pressure regulator and an internal pressure sensor to track and determine the hydrogen consumption. The reaction mixture was then stirred at 25℃and 1 bar hydrogen pressure (1000 revolutions per minute), the pressure being maintained at this value throughout the reaction. After the completion of the alkyne hydrogenation (2 to 3 hours), also determined by GC analysis through a short polar column (DB-Wax 10m X0.1mm X0.1 μm), stirring was stopped and the autoclave was depressurized and purged with nitrogen (3 times 5 bar). The reaction mixture was passed through some filtration equipment to remove Lindlar catalyst and transferred to a round bottom flask for solvent removal under vacuum. The desired 1-vinyl-4, 4-dimethylcyclohexanol was obtained with a GC conversion of over 99.5% and a GC purity of 93-95% and without formation of residue (as determined by sample ball-to-ball distillation).

CDCl ₃ In (a) and (b) ¹ The results of the H-NMR analysis are consistent with literature data (see Angew. Chem. Int. Ed.2009,48, 3146-3149)

¹³ C NMR(90MHz,CDCl ₃ ):δ25.5,29.4,30.9,33.7,34.7,71.5,111.6,146.1。

b) Step 2: preparation of 4, 4-dimethyl-1-vinylcyclohexyl acetate

At N ₂ To a stirred solution of 4, 4-dimethyl-1-vinyl-cyclohexanol (13.6 g, 96% pure, 84.8 mmol) and acetic anhydride (26.77 g,254.3 mmol) in toluene (30 mL) was added DMAP (104 mg,0.85mmol,1 mol%) and triethylamine (8.6 g,84.8 mmol). The mixture was heated to 90 ℃. After 5 hours, DMAP (104 mg,0.85mmol,1 mol%) was added and the mixture was stirredThe mixture was stirred for an additional 5 hours. The mixture was cooled in a cold water bath (10 ℃) and 30mL of water (residual Ac) was slowly added ₂ Hydrolysis of O). After stirring for 30 minutes, 50mL of diethyl ether was added. The phases were separated and the organic phase was washed once with 1M aqueous HCl (40 mL), then once with water (50 mL), then with saturated NaHCO ₃ The aqueous solution (50 mL) was washed twice. After the last washing with brine, the organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure (45 ℃ C., 30 mbar). The crude product was purified by flash chromatography (330 g SiO) ₂ Eluting from cyclohexane 95/diisopropyl ether 5 to cyclohexane 9/AcOEt 1). 4, 4-dimethyl-1-vinylcyclohexyl acetate (14.93 g, 97% purity, 78.4mmol, 92.5% yield) was isolated as a colourless liquid (volatile).

¹ H-NMR(300MHz):0.90,0.94(2x s,6H,4-(CH ₃ ) ₂ ),1.19–1.27(m,2H,H-3a,H-5a),1.36–1.45(m,2H,H-3b,H-5b),1.62–1.72(m,2H,H-2a,H-6a),2.0(s,1H,COCH ₃ ),2.05–2.14(m,2H,H-2b,H-6b),5.12(dd,1H, ² J _2’a,2’b ＝0.9Hz； ³ J _1’,2’a ＝11.0Hz,H-2’a),5.17(dd,1H, ² J _2’a,2’b ＝0.9Hz； ³ J _1’,2’b ＝17.7Hz,H-2’b),6.11(dd,1H, ³ J _1’,2’a ＝11.0Hz, ³ J _1’,2’b ＝17.7Hz,H-1’)。

¹³ C-NMR(100.61MHz):22.1(COCH ₃ ),25.6,31.0((CH ₃ ) ₂ ),29.3(C-4),30.8(C-2,C-6),34.7(C-3,C-5),81.6(C-1),113.6(C-2’),141.7(C-1’),169.9(C＝O)。

Example 2

Preparation of 4, 4-dimethyl-1-vinylcyclohexyl acetate by esterification and then hydrogenationa) Step 1: preparation of 1-ethynyl-4, 4-dimethylcyclohexyl acetate

1-ethynyl-4, 4-dimethylcyclohexanol (CAS number: 68483-62-5), acetonitrile (100 wt%) and acetic anhydride (1.3 equivalents) were charged together into a round bottom flask equipped with a magnetic stirrer bar and an internal temperature sensor. The reaction mixture was cooled to 3℃and solid para-formaldehyde was added in portionsIron (III) benzenesulfonate hexahydrate (CAS number 312619-41-3) (2 mol.%) to maintain the temperature below 10 ℃. Analysis by GC was performed after the reaction by a short nonpolar column (DB-1 10m X0.1mm X0.1 μm) under such conditions that complete conversion was achieved within 3 hours, yielding a crude product with GC selectivity of 98%. The reaction mixture was warmed to room temperature and the light compounds were removed under vacuum. Et is added to ₂ O (160 wt%) was added to the concentrated crude product, and the solution was taken up in 10% Na ₂ CO ₃ Aqueous solution, water, 1%H ₂ SO ₄ Aqueous solution and water wash. At Na (Na) ₂ SO ₄ After drying, et is removed in vacuo ₂ O. In Primol ^TM 352 was purified by flash evaporation in the presence of a ballasting agent and then the final light compounds were further removed by fractional distillation to give the desired pure 1-ethynyl-4, 4-dimethylcyclohexyl acetate in a molar yield of 90%.

¹ H NMR(500MHz,CDCl ₃ ):δ(ppm)0.93(s,3H,CH ₃ ),0.95(s,3H,CH ₃ ),1.33-1.41(m,2H,CH ₂ ),1.42-1.52(m,2H,CH ₂ ),1.90-2.02(m,2H,CH ₂ ),2.02-2.14(m,5H,CH ₂ +CH ₃ ),2.58(s,1H,CH)。

¹³ C NMR(125MHz,CDCl ₃ ):δ(ppm)21.9(CH ₃ ) 27.2 (broad peak signal, CH ₃ ) 29.1 (broad peak signal, CH ₃ ),29.3(C),32.8(CH ₂ ),35.1(CH ₂ ),73.9(CH),75.1(C),83.5(C),169.3(CO)。

b) Step 2: preparation of 4, 4-dimethyl-1-vinylcyclohexyl acetate

1-ethynyl-4, 4-dimethylcyclohexyl acetate (unknown compound), acetone (100 wt%), lindlar catalyst (0.75 wt%, 0.068mol.% Pd) and 3, 6-dithio-1, 8-octanediol (Lindlar catalyst poison, CAS No. 5244-34-8) (0.00765 wt%, 12mol.% relative to Pd) were charged together into a 100mL or 1L autoclave equipped with mechanical fixtures, pressure and internal temperature sensors and a heating/cooling system for internal temperature regulation. The sealed autoclave was then purged with nitrogen (3 times 5 bar) with stirring, then stirred at 25 ℃ and 1 bar nitrogen pressure for 30 minutes. After this time, the autoclave was purged with hydrogen (3 times 1 bar) with stirring, and then pressurized to a hydrogen pressure of 1 bar by a hydrogen tank equipped with an outlet pressure regulator and an internal pressure sensor to track and determine the hydrogen consumption. The reaction mixture was then stirred at 25℃and 1 bar hydrogen pressure (1000 revolutions per minute), the pressure being maintained at this value throughout the reaction. After the completion of the alkyne hydrogenation (5 to 7 hours), also determined by GC analysis through a short polar column (DB-Wax 10m X0.1mm X0.1 μm), stirring was stopped and the autoclave was depressurized and purged with nitrogen (3 times 5 bar). The reaction mixture was passed through some filtration equipment to remove Lindlar catalyst and transferred to a round bottom flask for solvent removal under vacuum. The desired 4, 4-dimethyl-1-vinylcyclohexyl acetate was obtained with GC conversion exceeding complete, GC purity of 97.5% and no residue formed (determined by sample ball-to-ball distillation).

Example 3

Preparation of 4, 4-dimethyl-1-vinylcyclohex-1-ene

At N ₂ Under an air stream, 46.5g (purity 99.1%,234.8mmol 4, 4-dimethyl-1-vinylcyclohexyl acetate) was slowly (12 mL/h) added from the top to a heated pyrolysis column (pyrolysis furnace at 500 ℃) equipped with a 20g quartz cylinder. After the addition was completed, the oven was cooled. When the oven temperature of 50 ℃ was reached, the crude product was transferred to a separatory funnel and 50mL of pentane was added. The mixture was washed twice with 50mL of water and 100mL of saturated NaHCO ₃ The aqueous solution was washed once. The organic phase was dried over sodium sulfate and pentane was carefully evaporated (900 mbar, rotavap bath temperature 40 to 80 ℃). 35.1g of a yellow liquid are obtained (conversion 99%, GC purity 98.1%). The crude product was distilled (vigreux column, 50-20 mbar, boiling point 76 ℃) to give 29.23g (purity 99.0%,232.42mmol, yield 90.5%) of volatile 4, 4-dimethyl-1-vinylcyclohex-1-ene.

CDCl ₃ In (a) and (b) ¹ H and analysis results are consistent with literature data (see Angew. Chem. Int. Ed.2009,48, 3146-3149)

¹³ C NMR(90MHz,CDCl ₃ ):δ21.6,28.2,29.0,35.2,39.8,109.7,128.8,134.8,139.9。

Example 4

Hydroformylation of 4, 4-dimethyl-1-vinylcyclohexyl acetate

4, 4-dimethyl-1-vinylcyclohexyl acetate (196 mg,1.0 mmol), ligand (3.5 mM,2.0mL in EtOAc) and Rh (acac) (CO) ₂ (1.0 mM in EtOAc, 1.43 mL) was added to an autoclave (HEL 20mL/200 bar). The autoclave was purged 3 times with 8 bar argon with 10 bar synthesis gas (H) with stirring (500 rpm) ₂ CO, 1:1) 4 times. The autoclave was then charged with 10 bar synthesis gas and the reaction mixture was heated until the temperature reached 75 ℃. The autoclave was then further pressurized with synthesis gas to 40 bar, the stirring rate was adjusted to 900rpm and the temperature was set to 80 ℃. Continuing the hydroformylation with H ₂ CO (1:1) compensates for gas absorption. After 22 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged 5 times with 12 bar argon. Product analysis was performed by gas chromatography using tetradecane as internal standard.

The results obtained are shown in Table 1.

Table 1: hydroformylation of 4, 4-dimethyl-1-vinylcyclohexyl acetate catalyzed by rhodium complexes with different ligands.

1) Determined by GC; 1 is 4, 4-dimethyl-1- (3-oxopropyl) cyclohexyl acetate and 2 is 4, 4-dimethyl-1- (1-oxopropan-2-yl) cyclohexyl acetate

4, 4-dimethyl-1- (3-oxopropyl) cyclohexyl acetate (1)

¹ H-NMR(300MHz):0.86,0.90(2x s,6H,4-(CH ₃ ) ₂ ),1.14–1.21(m,2H,H-3a,H-5a),1.27–1.47(m,4H,H-3b,H-5b,H-2a,H-6a)；2.0(s,3H,COCH ₃ ),2.03–2.11(m,2H,H-2b,H-6b),2.18–2.23(m,2H,H-3’),2.37–2.43(m,2H,H-2’),9.72(t,1H, ³ J _1’,2’ ＝1.7Hz,H-1’)。

¹³ C-NMR(100.61MHz):22.0(CH ₃ CO),25.3,31.0((CH ₃ ) ₂ ),29.3(C-3’),29.3(C-4),30.4(C-2,C-6),34.5(C-3,C-5),38.2(C-2’),82.6(C-1),170.3(COCH ₃ ),201.8(C-1’)。

4, 4-dimethyl-1- (1-oxopropan-2-yl) cyclohexyl acetate (2)

¹ H-NMR(500MHz):0.86,0.89(2x s,6H,4-(CH ₃ ) ₂ ),1.03(d,3H, ³ J _2’,3’ ＝7.1Hz,3’-CH ₃ ),1.17–1.23(*,2H,H-3a,H-5a),1.31–1.43(*,2H,H-3b,H-5b),1.54,1.63(2x ddd,1H, ³ J _2a,3b ＝ ³ J _6a,5b ＝4.0Hz, ³ J _2a,3a ＝ ³ J _5a,6a ＝13.0Hz, ² J _2a,2b ＝ ² J _6a,6b ＝14.0Hz,H-2a’,H-6a’),2.0(s,1H,COCH ₃ ),2.04–2.09,2.17–2.21(*,2H,H-2b,H-6b),3.22(dq,1H, ³ J _1’,2’ ＝1.6Hz, ³ J _2’,3’ ＝7.1Hz,H-2’)；9.73(d,1H, ³ J _1’,2’ =1.64 hz, h-1').) signal according to the main product.

¹³ C-NMR(125.76MHz):8.5(3’-CH ₃ ),21.7(CH ₃ CO),24.2,32.0((CH ₃ ) ₂ ),29.2(C-4)；27.1,28.9(C-2,C-6),34.1,34.2(C-3,C-5),51.5(C-2’),83.7(C-1),170.4(COCH ₃ ),202.3(C-1’)。

Example 5

Hydroformylation of 4, 4-dimethyl-1-vinylcyclohexyl acetate using Xantphos-Rh catalyst

a) General procedure:

according to Table 2, acetic acid 4, 4-dimethyl-1-vinylcyclohexyl ester (589 mg,3.0 mmol), xantphos (i.e., (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine) (in EtOAc) and Rh (acac) (CO) ₂ Added to an autoclave (HEL 20mL/200 bar) (in EtOAc). The autoclave was purged 3 times with 8 bar argon with 10 bar synthesis gas (H) with stirring (500 rpm) ₂ CO, 1:1) 4 times. The autoclave was then charged with 10 bar of synthesis gasThe reaction mixture was heated to a temperature of 75 ℃. The autoclave was then further pressurized with synthesis gas to 40 bar and the stirring speed was adjusted to 900rpm and the temperature set at 80 ℃. Continuing the hydroformylation with H ₂ CO (1:1) compensates for gas absorption. After the reaction time shown in table 2, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged 5 times with 12 bar argon. Product analysis was performed by gas chromatography using tetradecane as internal standard.

The results obtained are shown in Table 2.

Table 2: hydroformylation of 4, 4-dimethyl-1-vinylcyclohexyl acetate catalyzed by Xantphos-Rh catalysts under different catalyst supports.

Example 6

Hydroformylation of 4, 4-dimethyl-1-vinylcyclohexyl acetate using biphenphos-Rh catalyst

a) General procedure:

according to Table 2, 4-dimethyl-1-vinylcyclohexyl acetate (785 mg,4.0 mmol), BIPHEPHOS (i.e. 6,6' - [ (3, 3' -di-tert-butyl-5, 5' -dimethoxy-1, 1' -biphenyl-2, 2' -diyl) bis (oxy)]Bis (dibenzo [ d, f)][1,3,2]Dioxaphosphepin)) (in EtOAc) and Rh (acac) (CO) ₂ Added to an autoclave (HEL 20mL/200 bar) (in EtOAc). The autoclave was purged 3 times with 8 bar argon with 10 bar synthesis gas (H) with stirring (500 rpm) ₂ CO, 1:1) 4 times. The autoclave was then charged with 10 bar of synthesis gas and the reaction mixture was heated until the temperature reached 85 ℃. The autoclave was then further pressurized with synthesis gas to 40 bar, the stirring rate was adjusted to 900rpm and the temperature was set to 90 ℃. Continuing the hydroformylation with H ₂ CO (1:1) make-up gasAbsorbing. After the reaction time shown in table 2, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged 5 times with 12 bar argon. Product analysis was performed by gas chromatography using tetradecane as internal standard.

The results obtained are shown in Table 3.

Table 3: hydroformylation of 4, 4-dimethyl-1-vinylcyclohexyl acetate catalyzed by a biphenhos-Rh catalyst under different catalyst loadings.

2)H ₂ :CO(2:1)

Example 7

Hydroformylation (amplification) of 4, 4-dimethyl-1-vinylcyclohexyl acetate using BIPHEPHOS-Rh

Rh (CO) ₂ acac (6.0 mM in EtOAc, 16.4 mL), BIPHEPHOS (15 mM in EtOAc, 33 mL), 4-dimethyl-1-vinylcyclohexyl acetate (39.0 g, 98.9% purity, 196.5 mmol) and ethyl acetate (3 mL) were added to an autoclave (Premex 150mL/200 bar) maintained under argon. The autoclave was charged with 10 bar synthesis gas (H ₂ CO, 1:1) and heating the reaction mixture with vigorous stirring until the temperature reached 90 ℃. The autoclave was then further pressurized with synthesis gas to 42 bar and the hydroformylation continued with H ₂ CO (1:1) compensates for gas absorption. After 3.5 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged with Ar. The mixture (94.8 g, gc 98% linear aldehyde 1,<0.1% branched aldehyde 2), yield 97%. Selective branched/linear 1/2 >98/0.1) was filtered and the solvent was evaporated under reduced pressure (150 mbar,45 ℃). After addition of 90mL of heptane and evaporation of the solvent (20 mbar,45 ℃ C.), 45.1g (purity 94.2%,187.7mmol, yield 95.5%) of 4, 4-dimethyl-1 acetate can be isolated as a yellow liquid- (3-oxopropyl) cyclohexyl ester.

Example 8

Hydrogenation of 4, 4-dimethyl-1-vinylcyclohexyl acetate using biphenhos analog-Rh catalyst Formylation

4, 4-dimethyl-1-vinylcyclohexyl acetate (491 mg,2.5 mmol), ligand (1.0 mM,0.25mL in EtOAc), rh (acac) (CO) ₂ (0.5 mM in EtOAc, 0.25 mL) and EtOAc (0.34 mL) were added to an autoclave (HEL 20mL/200 bar). The autoclave was purged 3 times with 8 bar argon with 10 bar synthesis gas (H) with stirring (500 rpm) ₂ CO, 1:1) 4 times. The autoclave was then charged with 10 bar of synthesis gas and the reaction mixture was heated until the temperature reached 85 ℃. The autoclave was then further pressurized with synthesis gas to 30 bar, the stirring rate was adjusted to 900rpm and the temperature was set to 90 ℃. Continuing the hydroformylation with H ₂ CO (1:1) compensates for gas absorption. After 20 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged 5 times with 12 bar argon. Product analysis was performed by gas chromatography using tetradecane as internal standard.

The results obtained are shown in Table 4.

Table 4: hydroformylation of 4, 4-dimethyl-1-vinylcyclohexyl acetate catalyzed by rhodium complexes with different ligands.

2) 2- ((3, 3 '-di-tert-butyl-2' - ((4, 8-di-tert-butyl-2, 10-dimethoxy dibenzo [ d, f ] [1,3,2] dioxaphosphepin-6-yl) oxy) -5,5 '-dimethoxy- [1,1' -biphenyl ] -2-yl) oxy) -4H-naphtho [2,3-d ] [1,3,2] dioxaphosphepin-4-one; prepared according to angel. Chem,2001,113,1739-1741.

3) 2- ((3, 3 '-di-tert-butyl-2' - ((4, 8-di-tert-butyl-2, 10-dimethoxy dibenzo [ d, f ] [1,3,2] dioxaphosphepin-6-yl) oxy) -5,5 '-dimethoxy- [1,1' -biphenyl ] -2-yl) oxy) -8-methyl-4H-benzo [ d ] [1,3,2] dioxaphosphepin-4-one; prepared according to angel. Chem,2001,113,1739-1741.

4) 8-methyl-2- ((3, 3', 5' -tetra-tert-butyl-2 '- ((2, 4,8, 10-tetra-tert-butyldibenzo [ d, f ] [1,3,2] dioxaphosphepin-6-yl) oxy) - [1,1' -biphenyl ] -2-yl) oxy) -4H-benzo [ d ] [1,3,2] dioxaphosphepin-4-one; prepared according to angel. Chem,2001,113,1739-1741.

5) 2- ((3, 3 '-di-tert-butyl-2' - ((4, 8-di-tert-butyl-2, 10-dimethoxy dibenzo [ d, f ] [1,3,2] dioxaphosphepin-6-yl) oxy) -5,5 '-dimethoxy- [1,1' -biphenyl ] -2-yl) oxy) -8-isopropyl-5-methyl-4H-benzo [ d ] [1,3,2] dioxaphosphepin-4-one; prepared according to angel. Chem,2001,113,1739-1741.

Example 9

Preparation of 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal

At N ₂ Under a stream of air, 3g (GC purity 97%,12.86 mmol) of 4, 4-dimethyl-1- (3-oxopropyl) cyclohexyl acetate in 12g of cyclohexane were slowly (12 mL/h) fed from the top into a heated pyrolysis column (pyrolysis furnace at 500 ℃) equipped with a 20g quartz cylinder (Raschig 4 mm). After the addition was complete, the oven was cooled and the quartz cylinder was washed with 5g cyclohexane. 20g of a mixture was obtained, which was analyzed by GC for the volatility of the product (GC purity 75.7%)>3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal was estimated as: 9.70mmol, 75% yield, 14.4% GC purity>3- (4, 4-dimethylcyclohexylidene) propanal was estimated to be 0.31mmol,1.84mmol, 14.3% yield and GC purity 4.3%)>4, 4-dimethyl-1- (3-oxopropyl) cyclohexyl acetate was estimated to be 0.55mmol, yield 4.3%).

Work-up (work up with saturated NaHCO) ₃ Aqueous solution and water), the volatile product mixture can be purified by column chromatography.

3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal

¹ H-NMR(300.13MHz):0.86(s,6H,4’-(CH ₃ ) ₂ ),1.34(t,2H, ³ J _5’,6’ ＝6.4Hz,H-5’),1.75(m,2H,H-3’),1.88–1.94(m,2H,H-6’),2.28(m,2H,H-3),2.48–2.54(m,2H,H-2),5.32(m,1H,H-2’),9.74(t,1H, ² J _1,2 ＝2.0Hz,H-1)。

¹³ C-NMR(75.47MHz):26.2(C-6’),28.1(CH ₃ ),28.4(C-4’),29.7(C-3),35.5(C-5’),39.1(C-3’),41.9(C-2),120.9(C-2’),134.2(C-1’),202.7(C-1)。

3- (4, 4-dimethylcyclohexylidene) propanal

¹³ C NMR(125MHz,CDCl ₃ ):δ25.0,28.1,30.6,32.8,40.0,40.8,42.6,109.5,145.6,200.2。

Example 10

Preparation of 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4, 4-dimethylcyclohexyl acetate

Under dean-Stark conditions in 50mL of toluene in 13.9g (212.0 mmol,1.5 eq.) of ethylene glycol and 962mg of KHSO ₄ (7.1 mmol,5 mol%) in the presence of 34.1g (purity 94.2%,141.4 mmol) of 4, 4-dimethyl-1- (3-oxopropyl) cyclohexyl acetate were stirred at 105 to 113℃for 1 hour (internal temperature, water removal in 1 hour). The mixture was cooled to room temperature and 150mL of diethyl ether was added. With 75mL of water, 75mL of saturated NaHCO ₃ After washing with aqueous solution and 75ml of brine, the organic phase was washed with Na ₂ SO ₄ Dried and the solvent was evaporated under reduced pressure (crude 39.5 g). Kugelrohr distillation of the crude product gave two fractions containing 33.8g (125.0 mmol) of 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4, 4-dimethylcyclohexyl acetate and 1.71g (8.15 mmol) of (2- (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolan (yield 94.2%,133.15 mmol).

Acetic acid 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4, 4-dimethylcyclohexyl ester:

¹ H-NMR(500.15MHz):0.89(s,3H),0.92(s,3H),1.18-1.23(m,2H,1.33-1.39(m,2H),1.43-1.51(m,2H),1.61-1.66(m,2H),1.99-2.02(m,2H),2.00(s,3H),2.08-2.14,(m,2H),3.81-3.88(m,2H).3.93-4.00(m,2H),4.83(t,1H,J＝4.8Hz)。

¹³ C NMR(150MHz,CDCl ₃ ):δ22.2,25.4,29.4,29.4,30.5,31.1,34.6,38.3,82.8,170.4,201.9。

(2- (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane:

¹³ C NMR(125MHz,CDCl ₃ ):δ26.2,28.2,28.5,31.8,32.2,35.7,39.3,64.9,104.5,120.1,135.4。

example 11

Preparation of (2- (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane

66mg (0.349 mmol,5 mol%) of pTsOH H are stirred under dean-Stark conditions (reflux) in 20mL of toluene ₂ O was heated at 110℃for 30 minutes. 1.9g (purity 98.7%,6.93 mmol) of 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4, 4-dimethylcyclohexyl acetate are slowly added over 1 hour. The mixture was stirred for a further hour to isomerise the exo double bond to an endo double bond. After cooling to room temperature, 30ml of diethyl ether was added. With 5mL saturated NaHCO ₃ After washing with aqueous solution and 10ml of brine, the organic phase was washed with Na ₂ SO ₄ Drying and evaporation of the solvent under reduced pressure (crude 1.53 g). Kugelrohr distillation of the crude product gave two fractions containing 1.29g of (2- (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane (6.13 mmol, 89% yield), 68mg of 2- (2- (4, 4-dimethylcyclohexylidene) ethyl) -1, 3-dioxolane (0.323 mmol, 4.6% yield) and 14mg of 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal (0.0842 mmol, 1.2% yield).

(2- (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane (internal): ¹ H-NMR(500.15MHz):0.88(s,3H),1.35(t,2H,J＝6.5Hz),1.74-1.79(m,4H),1.92-1.97(m,2H),2.07(t,2H,J＝8.3Hz),3.82-3.88(m,2H),3.93-4.00(m,2H),4.86(t,1H,J＝4.9Hz),5.34(m,1H)。

2- (2- (4, 4-dimethylcyclohexylidene) ethyl) -1, 3-dioxolane (exo)

¹³ C NMR(100MHz,CDCl ₃ ):δ24.8,28.2,30.6,32.3,32.9,40.1,40.9,64.9,104.6,114.0,142.8。

3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal

Example 12

Preparation of (2- (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane

At N ₂ 2g (7.39 mmol) of 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4, 4-dimethylcyclohexyl acetate were slowly (12 mL/h) fed from the top under gas flow into a heated pyrolysis column (pyrolysis furnace at 500 ℃) equipped with an 18g quartz cylinder (Raschig 4 mm). After the addition was complete, the oven was cooled and the quartz cylinder was washed with 10ml of cyclohexane. After addition of an additional 20mL of cyclohexane, the mixture was treated with 10mL of saturated NaHCO ₃ The aqueous solution was washed twice. The aqueous phases were combined and extracted once with 10mL of cyclohexane. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure (Rotavap 10mbar,45 ℃). 1.452g of a product (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane, 4.87mmol, yield 65.9%, 2- (2- (4, 4-dimethylcyclohexylidene) ethyl) -1, 3-dioxolane, 1.70mmol, yield 23.0%, 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal, 0.0148mmol, yield 1.5%) having a purity of 70.6% were obtained.

The amount of 2- (2- (4, 4-dimethylcyclohexylidene) ethyl) -1, 3-dioxolane can be determined by 5mol% pTsOH.H in 15mL of toluene ₂ Heating at 110℃in the presence of O. After 3 hours, we obtained 94.0% 2- (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane, 3.7% 2- (2- (4, 4-dimethylcyclohexylidene) ethyl) -1, 3-dioxolane and 0.2% 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal by GC analysis.

Example 13

Preparation of 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal

6.24g of (2- (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane (purity 91.7%,27.20mmol, containing 1.08mmol of 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal), 9.25g of AcOH (155.7 mmol,5.5 eq) and 9.25g of water (719 mmol,19.1 eq) are heated in 9.1mL of heptane with stirring for 3 hours at 85℃under reflux, after cooling to room temperature, 25mL of diethyl ether are added, the acetic acid is neutralized with 25% aqueous NaOH at 10℃to pH 6, the organic phase is separated and saturated NaHCO with 15mL ₃ The aqueous solution and 15mL brine wash. With Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure (500-100 mbar, 40 ℃). By flash chromatography (220 g of SiO ₂ The crude product (still containing some heptane) was purified by eluting from pentane to pentane 9/diisopropyl ether 1. 3.348g (purity 98%,19.73mmol, yield 69.8%) of 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal were obtained, and 1.46g (purity 90.0%,6.25mmol, yield 22.1%) of the starting material (2- (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane was recovered.

3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal was obtained from 1-ethynyl-4, 4-dimethylcyclohexanol in the order reported in examples 2, 6, 8, 9 and 11 in a total yield of at least 60%. Whereas 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal was obtained starting from 4, 4-dimethyl-cyclohexanol in an overall yield of 27% as reported in EP 1529770. The process of the present invention allows the production of 3- (cyclohex-1-en-1-yl) propanal derivatives in improved yields.

Example 14

Hydroformylation of 4, 4-dimethyl-1-vinylcyclohex-1-ene

4, 4-dimethyl-1-vinylcyclohex-1-ene (136 mg,1.0 mmol), ligand (3.5 mM,2.0mL in EtOAc) and Rh (acac) (CO) ₂ (1.0 mM in EtOAc, 1.43 mL) was added to an autoclave (HEL 20mL/200 bar). The autoclave was purged 3 times with 8 bar argon with 10 bar synthesis gas (H) with stirring (500 rpm) ₂ CO, 1:1) 4 times. The autoclave was then charged with 10 bar synthesis gas and the reaction mixture was heated until the temperature reached 75 ℃. The autoclave was then further pressurized with synthesis gas to 40 bar, the stirring rate was adjusted to 900rpm and the temperature was set to 80 ℃. Continuing the hydroformylation with H ₂ CO (1:1) compensates for gas absorption. After 22 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged 5 times with 12 bar argon. Product analysis was performed by gas chromatography.

The results obtained are shown in Table 5.

Table 5: hydroformylation of 4, 4-dimethyl-1-vinylcyclohex-1-ene catalyzed by rhodium complexes having different ligands.

1) Determined by GC; 3 is 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal, 4 is 2- (4, 4-dimethylcyclohex-1-en-1-yl) propanal, 5 is 2- (4, 4-dimethylcyclohexylidene) propanal, 6 is 6-ethylene-3, 3-dimethylcyclohex-1-en, and 7 is 1-ethyl-4, 4-dimethylcyclohex-1-en.

3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal (3)

2- (4, 4-dimethylcyclohex-1-en-1-yl) propanal (4)

¹ H-NMR(500.13MHz):0.89(2x s,6H,4’-(CH ₃ ) ₂ ),1.16(d,3H, ³ J _2,3 ＝7.0Hz,3-CH ₃ ),1.37(t,2H, ³ J _5’,6’ ＝6.4Hz,H-5’),1.85(m,2H,H-3’),1.86–1.88,1.96–2.02(2x m,2H,H-6’),2.93(q,1H, ² J _1,2 ＝1.7Hz, ² J _2,3 ＝7.0Hz,H-2),5.51(m,1H,H-2’),9.49(d,1H, ² J _1,2 ＝1.7Hz,H-1)。

¹³ C-NMR(125.76MHz):12.1(3-CH ₃ ),25.0(C-6’),28.2(4’-(CH ₃ ) ₂ ),28.4(C-4’),35.4(C-5’),39.4(C-3’),54.1(C-2),125.0(C-2’),132.7(C-1’),202.1(C-1)。

6-ethylene-3, 3-dimethylcyclohex-1-ene (6)

¹ H-NMR (400.13 MHz,2 isomers) 1.01,1.02 (4 x s,6H,4' - (CH) ₃ ) ₂ ),1.50(t,2H, ³ J _5’,6’ ＝6.2Hz,H-5’),1.67(d,3H, ³ J _1,2 ＝7.0Hz,H-2),2.29,2.33(2x t,2H,1H, ³ J _5’,6’ ＝6.2Hz,H-6’),5.20,5.33(2x q,1H, ³ J _1,2 ＝7.0Hz,H-1),5.40,5.54(2x d,1H, ³ J _2’,3’ ＝10.0Hz,H-3’),5.89,5.95(2x d,1H, ³ J _2’,3’ ＝10.0Hz,H-2’)。

¹³ C-NMR (100.63 MHz,2 isomers): 12.5,13.1 (C-2), 21.7 (C-6 '), 29.1,29.2 (4' -CH) ₃ ),32.0(C-4’),36.6,37.4(C-5’),121.2(C-1),128.3(C-2’),135.3(C-1’),137.2,139.6(C-3’)。

1-Ethyl-4, 4-dimethylcyclohex-1-ene (7)

¹ H-NMR(500.13MHz):0.89(s,6H,4’-(CH ₃ ) ₂ ),0.99(t,3H, ³ J _1,2 ＝7.5Hz,H-2),1.36(t,2H, ³ J _5’,6’ ＝6.5Hz,H-5’),1.77(m,2H,H-3’),1.95(m,2H,H-1),1.96(m,2H,H-6’),5.30(m,1H,H-2’)。

¹³ C-NMR(125.76MHz):12.5(C-2),26.1(C-1),28.2(2x CH ₃ ),28.6(C-4’),30.2(C-6’),35.8(C-5’),39.3(C-3’),118.3(C-2’),138.0(C-1’)。

Example 15

Hydroformylation of 4, 4-dimethyl-1-vinylcyclohex-1-ene using a biphenhos-Rh catalyst

a) General procedure:

according to table 6 (total volume of etoac=3.5 mL), 4-dimethyl-1-vinylcyclohex-1-ene (136 mg,1.0 mmol), biphenphos (in EtOAc) and Rh (acac) (CO) ₂ Added to an autoclave (HEL 20mL/200 bar) (in EtOAc). The autoclave was purged 3 times with 8 bar argon with 10 bar synthesis gas (H) with stirring (500 rpm) ₂ CO, 1:1) 4 times. The autoclave was then charged with 10 bar synthesis gas and the reaction mixture was heated until the temperature reached 95 ℃. The autoclave was then further pressurized with synthesis gas to 20 bar, the stirring rate was adjusted to 900rpm and the temperature was set to 100 ℃. Continuing the hydroformylation with H ₂ CO (1:1) compensates for gas absorption. After the reaction time shown in table 6, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged 5 times with 12 bar argon. Product analysis was performed by gas chromatography using tetradecane as internal standard.

The results obtained are shown in Table 6.

Table 6: hydroformylation of 4, 4-dimethyl-1-vinylcyclohex-1-ene catalyzed by biphenhos-Rh catalysts under different catalyst loadings.

2)H ₂ :CO(2:1)

Example 16

a) General procedure:

according to Table 3 (total volume of EtOAc=3.5 mL), 4-dimethyl-1-vinylcyclohex-1-ene (136 mg,1.0 mmol), BIPHEPHOS (in EtOAc) and HRh (CO) (PPh) ₃ ) ₃ Added to an autoclave (HEL 20mL/200 bar) (in EtOAc). The autoclave was purged 3 times with 8 bar argon with 10 bar synthesis gas (H) with stirring (500 rpm) ₂ CO, 1:1) 4 times. The autoclave was then charged with 10 bar synthesis gas and the reaction mixture was heated until the temperature reached 95 ℃. The autoclave was then further pressurized with synthesis gas to 20 bar, the stirring rate was adjusted to 900rpm and the temperature was set to 100 ℃. Continuing the hydroformylation with H ₂ CO (1:1) compensates for gas absorption. After 72 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged 5 times with 12 bar argon. Product analysis was performed by gas chromatography using tetradecane as internal standard.

The results obtained are shown in Table 7.

Table 7: hydroformylation of 4, 4-dimethyl-1-vinylcyclohex-1-ene catalyzed by biphenhos-Rh catalysts under different catalyst loadings.

2)H ₂ :CO(2:1)

Example 17

Hydroformylation of 4, 4-dimethyl-1-vinylcyclohex-1-ene using Xantphos-Rh catalyst

a) General procedure:

according to table 2 (total volume of etoac=3.5 mL, if no other volumes are indicated), 4-dimethyl-1-vinylcyclohex-1-ene (136 mg,1.0 mmol), xantphos (in EtOAc) and Rh (acac) (CO) ₂ Added to an autoclave (HEL 20mL/200 bar) (in EtOAc). The autoclave was purged 3 times with 8 bar argon with 10 bar synthesis gas (H) with stirring (500 rpm) ₂ CO, 1:1) 4 times. The autoclave was then charged with 10 bar of synthesis gas and the reaction mixture was heated until the temperature reached 65-105 ℃. The autoclave was then further pressurized with synthesis gas to 60 bar, the stirring rate was adjusted to 900rpm and the temperature was set to 70-110 ℃. Continuing the hydroformylation with H ₂ CO (1:1) compensates for gas absorption. After 72 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged 5 times with 12 bar argon. Product analysis was performed by gas chromatography.

The results obtained are shown in Table 8.

Table 8: hydroformylation of 4, 4-dimethyl-1-vinylcyclohex-1-ene catalyzed by Xantphos-Rh catalysts under different conditions.

2) Total volume of EtOAc = 0.9mL

Example 18

4, 4-dimethyl-1-vinylcyclohex-1-ene hydroformazan using Xantphos analog-Rh catalyst Acylation

a) General procedure:

4, 4-dimethyl-1-vinylcyclohex-1-ene (136 mg,1.0 mmol), ligand (3.5 mM,2.0mL in EtOAc) and Rh (acac) (CO) ₂ (0.67 mM in EtOAc, 1.49 mL) was added to an autoclave (HEL 20mL/200 bar). The autoclave was purged 3 times with 8 bar argon with 10 bar synthesis gas (H) with stirring (500 rpm) ₂ CO, 1:1) 4 times. The autoclave was then charged with 10 bar of synthesis gas and the reaction mixture was heated until the temperature reached 85 ℃. The autoclave was then further pressurized with synthesis gas to 60 bar, the stirring rate was adjusted to 900rpm and the temperature was set to 90 ℃. Continuing the hydroformylation with H ₂ CO (1:1) compensates for gas absorption. After 72 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged 5 times with 12 bar argon. Product analysis was performed by gas chromatography.

The results obtained are shown in Table 9.

Table 9: hydroformylation of 4, 4-dimethyl-1-vinylcyclohex-1-ene catalyzed by Xantphos analog-Rh catalyst.

2) (1 s, 1's) - (+) - (2, 7-di-tert-butyl-9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis ((2-methoxyphenyl) (phenyl) phosphine); prepared according to Tetrahedron,2020,76,131142.

3) (1 s, 1's) - (-) - (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (naphthalen-2-yl (phenyl) phosphine); prepared according to ACS Catalysis,2017,7,6162-6169.

4) (1 s, 1's) - (-) - (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis ((4-methoxyphenyl) (phenyl) phosphine); prepared according to ACS Catalysis,2017,7,6162-6169.

5) (1 s, 1's) - (-) - (2, 7-di-tert-butyl-9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis ((1-naphthyl) (phenyl) phosphine); prepared according to Tetrahedron,2020,76,131142.

6) (1 s, 1's) - (-) - (2, 7-di-tert-butyl-9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis ((4-methylphenyl) (phenyl) phosphine); prepared according to Tetrahedron,2020,76,131142.

Example 19

Will Rh (acac) (CO) ₂ A solution of (6.0 mM,4.6mL in EtOAc), BIPHEPHOS (14.6 mM,9.5mL in EtOAc) and 4, 4-dimethyl-1-vinylcyclohex-1-ene (3.75 g,27.52 mmol) in EtOAc (80 mL) was added to an autoclave (Premex 200mL/200 bar) maintained at 1 bar Ar. The autoclave was charged with 10 bar synthesis gas (H ₂ CO, 1:1) and heating the reaction mixture with vigorous stirring until the temperature reached 100 ℃. The autoclave was then further pressurized with synthesis gas to 23 bar and the hydroformylation continued with H ₂ CO (1:1) compensates for gas absorption. After 24 hours, the reaction mixture was cooled to room temperature, the pressure was released and the autoclave was purged with Ar. (GC yield (internal standard) 66%). The solvent was evaporated under reduced pressure (45 ℃ C., 200 mbar). The crude product was purified by flash chromatography (120 g SiO) ₂ Eluting from cyclohexane/AcOEt 99/1 to cyclohexane/AcOEt 95/5). 4.9g of the product 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal/2- (4, 4-dimethylcyclohex-1-en-1-yl) propanal 93/6 are obtained, which additionally contains some solvent. Kugelrohr distillation gave 2.90g of 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal (92.8% GC purity, 16.18mmol, 59% yield) and 2- (4, 4-dimethylcyclohex-1-en-1-yl) propanal (6.3% GC purity). Some products are lost due to volatility.

Example 20

Hydroformylation of 6-ethylene-3, 3-dimethylcyclohex-1-ene-side reactions formed during hydroformylation Recovery of product 6

6-ethylene-3, 3-dimethylcyclohexanes1-ene (136 mg,1.0 mmol), ligand (3.5 mM,2.0mL in EtOAc) and Rh (acac) (CO) ₂ (1.0 mM in EtOAc, 1.43 mL) was added to an autoclave (HEL 20mL/200 bar). The autoclave was purged 3 times with 8 bar argon with 10 bar synthesis gas (H) with stirring (500 rpm) ₂ CO, 1:1) 4 times. The autoclave was then charged with 10 bar synthesis gas and the reaction mixture was heated until the temperature reached 95 ℃. The autoclave was then further pressurized with synthesis gas to 20 bar, the stirring rate was adjusted to 900rpm and the temperature was set to 100 ℃. Continuing the hydroformylation with H ₂ CO (1:1) compensates for gas absorption. After the reaction time shown in table 6, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged 5 times with 12 bar argon. Product analysis was performed by gas chromatography.

The results obtained are shown in Table 10.

Table 10: hydroformylation of 6-ethylene-3, 3-dimethylcyclohex-1-ene catalyzed by biphenhos modified Rh catalysts.

1) Determined by GC; 3 is 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal, 4 is 2- (4, 4-dimethylcyclohex-1-en-1-yl) propanal, 5 is 2- (4, 4-dimethylcyclohexylidene) propanal, and 7 is 1-ethyl-4, 4-dimethylcyclohex-1-en.

2)H ₂ :CO＝1:2

3)H ₂ :CO＝2:1

4)H ₂ :CO＝3:1

Example 21

Preparation of different compounds of formula (II)

The starting materials 4- (tert-butyl) cyclohex-1-one (CAS 98-53-3, aldrich), 3-isopropylcyclohex-1-one (CAS 23396-36-3, aldrich), 4-butylcyclohex-1-one (CAS 61203-82-5, aurumpicatech), 2-ethyl-4, 4-dimethylcyclohex-1-one (CAS 55739-89-4, aurorafinechemics), 3-isopropylcyclohex-1-one (CAS 10264-56-9, alfa-chemistry) are commercially available or can be prepared according to literature procedures.

a) Step 1: preparation of vinyl alcohol by adding vinyl grignard reagent to cyclic substituted ketone

General procedure for addition of cyclic substituted ketones to vinyl magnesium chloride solution:

to a cooled solution of 196.6mL of vinyl magnesium chloride (1.6M in THF, 314.5mmol,1.1 eq.) and 150mL of THF (0 ℃) was slowly added a solution of cyclic ketone (285.9 mmol) in 60mL of THF. The internal temperature does not exceed 5 ℃ during the addition of the cyclic substituted ketone. The mixture was further stirred overnight (16 hours) at 0 ℃ and analyzed by GC. The reaction mixture was slowly added to a cooled solution of 21g AcOH (343.1 mmol) in 200ml water. The phases were separated and the aqueous phase was extracted with 150mL TBME. The combined organic phases were saturated with NaHCO ₃ Aqueous solution and saturated aqueous NaCl solution. With Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure (500-50 mbar,50 ℃). The crude product was purified by flash chromatography or by distillation through a Vigreux column under reduced pressure.

4- (tert-butyl) -1-vinylcyclohex-1-ol

The compound was prepared according to the general procedure and using 4- (tert-butyl) cyclohex-1-one as cyclic ketone.

GC crude product: 91.2% of 4- (tert-butyl) -1-vinylcyclohex-1-ol.

Purity (GC) after purification was 94.0% (yield 78%).

CDCl ₃ The NMR analysis results in (A) were consistent with literature data (N.Miralles, R.Alam, K.J.Szab. Mu. E.Fernndez, angew.chem.int.ed.2016,55, 4303-4307).

Trans-4- (tert-butyl) -1-vinylcyclohex-1-ol: major isomer (trans/cis of 52/48)

¹³ C NMR(100MHz,CDCl ₃ ):δ24.5,27.6,32.3,39.2,47.5,72.2,113.8,147.0。

Cis-4- (tert-butyl) -1-vinylcyclohex-1-ol: minor isomer ¹³ C NMR(100MHz,CDCl ₃ ):δ22.3,27.6,32.4,37.7,47.6,71.3,110.9,142.8。

3-IsoPropyl-1-vinylcyclohex-1-ol

The compound was prepared according to the general procedure and using 3-isopropylcyclohex-1-one (10% 4-isopropylcyclohex-1-one) as cyclic ketone.

GC crude product: 3-isopropyl-1-vinylcyclohex-1-ol of 82.6% purity was derived from 3-isopropyl-cyclohex-1-one (85.7% purity)

The purified purity (GC) of the trans/cis isomer mixture, which contained 10% of 4-isopropyl-1-vinylcyclohex-1-ol, was 88.8% (yield 86%).

(1 sr,3 sr) -3-isopropyl-1-vinylcyclohex-1-ol: major isomer (trans/cis of 51/49)

¹ H-NMR(500.15MHz):0.86(d,3H,J＝6.8Hz),0.87(d,3H,J＝6.8Hz),1.14(t,1H,J＝12.8Hz),1.28(s,1H),1.33-1.47(m,3H),1.34-1.53(m,1H),1.54-1.61(m,2H),1.62-1.68(m,2H),1.69-1.75(m,1H),5.00(dd,1H,J＝10.8Hz,J＝1.2Hz),5.23(dd,1H,J＝17.4Hz,J＝1.2Hz),5.94(dd,1H,J＝17.4Hz,J＝10.8Hz)。

¹³ C NMR(125MHz,CDCl ₃ ):δ19.5,19.7,21.5,28.7,32.6,37.0,38.5,40.6,72.4,110.7,147.2。

(1 sr,3 rs) -3-isopropyl-1-vinylcyclohex-1-ol: minor isomer

¹ H-NMR(500.15MHz):0.86(d,6H,J＝6.9Hz),0.89-1.01(m,1H),1.18-1.25(m,2H),1.27-1.38(m,1H),1.39-1.48(m,2H),1.58(s,1H),1.63-1.76(m,3H),1.78-1.88(m,2H),5.15(dd,1H,J＝10.8Hz,J＝1.2Hz),5.31(dd,1H,J＝17.6Hz,J＝1.3Hz),6.08(dd,1H,J＝17.5Hz,J＝10.8Hz)。

¹³ C NMR(125MHz,CDCl ₃ ):δ19.7,19.7,23.3,28.9,32.7,38.9,41.2,42.5,72.9,113.7,143.3。

4-isopropyl-1-vinylcyclohex-1-ol (mixture of trans/cis isomers): CDCl ₃ The NMR analysis results in (B) were consistent with literature data (C.A.Discolo, E.E.Touney, S.V.Pronin, J.Am.Chem.Soc.2019 141 (44), 17527-17532).

4-butyl-1-vinylcyclohex-1-ol

The compound was prepared according to the general procedure and using 4-butylcyclohex-1-one as cyclic ketone.

GC crude product: 96.1% of 4-butyl-1-vinylcyclohex-1-ol.

Purity (GC) after purification was 94.5% (yield 99%).

Trans-4-butyl-1-vinylcyclohex-1-ol: major isomer (trans/cis of 58/42)

¹ H-NMR(500.15MHz):0.89(t,3H,J＝7.0Hz),1.02-1.12(m,2H),1.17-1.36(m,7H),1.46-1.57(m,3H),1.68-1.78(m,2H),1.78-1.86(m,2H),5.13(dd,1H,J＝10.9Hz,J＝1.2Hz),5.31(dd,1H,J＝17.5Hz,J＝1.2Hz),6.07(dd,1H,J＝17.5Hz,J＝10.9Hz)。

¹³ C NMR(125MHz,CDCl ₃ ):δ14.1,23.0,29.5,29.5,35.5,36.3,37.9,72.4,113.4,143.4。

Cis-4-butyl-1-vinylcyclohex-1-ol: minor isomer

¹ H-NMR(500.15MHz):0.86-0.92(m,3H),1.16-1.36(m,12H),1.42-1.51(m,2H),1.56-1.64(m,4H),4.99(dd,1H,J＝10.8Hz,J＝1.3Hz),5.23(dd,1H,J＝17.4Hz,J＝1.3Hz),5.93(dd,1H,J＝17.4Hz,J＝10.8Hz)。

¹³ C NMR(125MHz,CDCl ₃ ):δ14.1,23.0,28.1,29.2,36.7,36.9,37.0,71.6,110.9,146.9。

2-ethyl-4, 4-dimethyl-1-vinylcyclohex-1-ol

The compound was prepared according to the general procedure and using 2-ethyl-4, 4-dimethylcyclohex-1-one as cyclic ketone.

GC crude product: 94.1% of 2-ethyl-4, 4-dimethyl-1-vinylcyclohex-1-ol.

Purity (GC) after purification was 95.5% (yield 85%).

(1 SR,2 SR) -2-ethyl-4, 4-dimethyl-1-vinylcyclohex-1-ol (major isomer, cis/trans 87/13)

¹ H-NMR(500.15MHz):0.83(t,3H,J＝7.3Hz),0.91(s,3H),0.95(s,3H),1.10-1.23(m,2H),1.27-1.43(m,4H),1.48-1.59(m,2H),1.61.1.70(m,1H),5.07(dd,1H,J＝10.8Hz,J＝1.4Hz),5.24(dd,1H,J＝17.3Hz,J＝1.4Hz),5.84(dd,1H,J＝17.3Hz,J＝10.8Hz)。

¹³ C NMR(125MHz,CDCl ₃ ):δ12.3,22.3,24.2,30.2,33.1,34.0,35.3,39.4,41.8,74.5,111.6,146.4。

(1 SR,2 RS) -2-ethyl-4, 4-dimethyl-1-vinylcyclohex-1-ol (minor isomer)

¹ H-NMR(500.15MHz):0.99(s,3H),1.74-1.80(m,1H),5.14(dd,1H,J＝11.0Hz,J＝1.7Hz),5.31(dd,1H,J＝17.3Hz,J＝1.7Hz),6.19(dd,1H,J＝17.3Hz,J＝11.0Hz)。

¹³ C NMR(125MHz,CDCl ₃ ):δ12.2,22.3,25.1,30.6,32.8,36.6,37.5,41.8,44.8,75.5,113.3,139.5。

3-isopropyl-1-vinylcyclopent-1-ol

The compound was prepared according to the general procedure and using 3-isopropylcyclopent-1-one as cyclic ketone.

GC crude product: 94.8% of 3-isopropyl-1-vinylcyclopent-1-ol (isomer mixture (cis/trans) of 57/43).

Purity (GC) after purification was 96.7% (yield 84%).

(1 SR,3 RS) -3-isopropyl-1-vinylcyclopent-1-ol/(1 SR,3 SR) -3-isopropyl-1-vinylcyclopent-1-ol (cis/trans 57/43)

¹ H-NMR (500.15 MHz): 0.88 major isomer (d, 3H, j=6.4 Hz), 0.89 minor isomer (d, 1.5H J =6.6 Hz), 0.90 minor isomer (d, 1.5H, j=6.6 Hz), 1.31-1.85 (m, 7.5H), 1.94-2.05 (m, 1.5H), 5.00 major isomer (dd, 0.5H, j=10.7 Hz, j=1.2 Hz), 5.01 minor isomer (dd, 0.5H, j=10.7 Hz, j=1.3 Hz), 5.23 major isomer (dd, 0.5H, j=17.3 Hz, j=1.2 Hz), 5.26 minor isomer (dd, 0.5H, j=17.3 Hz, j=1.3 Hz), 6.01 (dd, 0.5H, j=17.5 Hz), 5.01 minor isomer (dd, j=17.5H, j=7.7 Hz).

¹³ C NMR(125MHz,CDCl ₃ ):δ21.2,21.3,21.4,21.6,28.7,29.5,33.7,34.1,39.7,40.8,45.0,45.6,45.6,46.7,29.5,34.0,40.8,45.6,46.7,82.3,110.9,145.0,81.6,82.3,110.5,110.9,144.7,145.0。

b) Step 2: preparation of vinyl acetate from vinyl alcohol (Compound of formula (II))

Using the alcohol prepared in example 21 a), the procedure from example 1b was used for the preparation of vinyl acetate. To prepare 2-ethyl-4, 4-dimethyl-1-vinylcyclohexyl acetate, the solvent was switched from toluene to THF and 5mol% DMAP was used (21% conversion after one day). The crude product was purified by flash chromatography or by distillation through a Vigreux column under reduced pressure.

Acetic acid 4- (tert-butyl) -1-vinylcyclohexyl ester

The compound was prepared according to the general procedure and using trans-4- (tert-butyl) -1-vinylcyclohex-1-ol/cis-4- (tert-butyl) -1-vinylcyclohex-1-ol as starting alcohol.

GC crude product: 89.7% of 4- (tert-butyl) -1-vinylcyclohexyl acetate was derived from 4- (tert-butyl) -1-vinylcyclohex-1-ol (purity 94.0%).

Purity (GC) after purification was 98.2% (86% yield).

CDCl of trans isomer ₃ The NMR analysis results in (b) were consistent with literature data (J.C.Fiaud, J.Y.Legros, J.Organomet.Chem.1989,370,383).

Trans-4- (tert-butyl) -1-vinylcyclohexyl acetate/cis-4- (tert-butyl) -1-vinylcyclohexyl acetate (trans/cis 54.5/44.5)

¹ H-NMR (500.15 MHz) 0.83 major isomer (s, 5H), 0.87 minor isomer (s, 4H), 0.98-1.16 (m, 2H), 1.21-1.29 (m, 1H,1.32-1.42 (m, 1H), 1.55-1.73 (m, 3H), 1.95 major isomer (s, 1.6H), 2.03 minor isomer (s, 1.4H), 2.34-2.47 (m, 2H), 5.08 (d, 0.5H, J=11.0 Hz), 5.12 (d, 0.5H, J=17.7 Hz), 5.30 (d, 0.5H, J=10.1 Hz), 5.32 (d, 0.5H, J=16.9 Hz), 6.10 minor isomer (dd, 0.5H, J=17.7 Hz, J=11.0 Hz), 6.15 dd=11.0 Hz, J=17.7 Hz, 5.5 Hz.

Trans-4- (tert-butyl) -1-vinylcyclohexyl acetate

¹³ C NMR(100MHz,CDCl ₃ ):δ22.4,24.1,27.5,32.2,36.0,47.5,82.1,116.6,139.3,169.7。

Cis-4- (tert-butyl) -1-vinylcyclohexyl acetate

¹³ C NMR(100MHz,CDCl ₃ ):δ22.0,22.3,27.5,32.4,35.0,47.0,81.3,112.8,142.3,169.9。

Acetic acid 3-isopropyl-1-vinylcyclohexyl ester

The compound was prepared according to the general procedure and using (1 sr,3 sr) -3-isopropyl-1-vinylcyclohex-1-ol/(1 sr,3 rs) -3-isopropyl-1-vinylcyclohex-1-ol as starting alcohol (10% 4-isopropyl-1-vinylcyclohex-1-ol, trans/cis isomer mixture).

GC crude product: 83.8% of acetic acid 3-isopropyl-1-vinylcyclohexyl ester was derived from 3-isopropyl-1-vinylcyclohex-1-ol (purity 88.8%).

Purity (GC) after purification was 88.7% (yield 83%, isomer mixture (cis/trans) of 42/47).

Acetic acid (1 SR,3 RS-3-isopropyl-1-vinylcyclohexyl/acetic acid (1 SR,3 SR) -3-isopropyl-1-vinylcyclohexyl (mixture of trans/cis isomers with 10% acetic acid 4-isopropyl-1-vinylcyclohexyl).

¹ H-NMR (500.15 MHz): 0.86 (d, 3H, j=5.8 Hz), 0.87 (d, 3H, j=5.8 Hz), 0.90-1.08 (m, 1H), 1.17-1.76 (m, 7H), 1.95 minor isomer (s 1.5H), 2.03 major isomer (s, 1.5H), 2.28-2.45 (m, 2H), 5.08 (d, 0.5H, j=11.0 Hz), 5.12 (d, 0.5H, j=17.7 Hz), 5.28 (d, 0.5H, j=10.0 Hz), 5.31 (d, 0.5H, j=17.1 Hz), 6.10 major isomer (dd, 0.5H, j=17.7 Hz, j=11.0 Hz), 6.16 minor isomer (dd, 0.5H, j=17.7 Hz).

Acetic acid (1 sr,3 sr) -3-isopropyl-1-vinylcyclohexyl ester: trans isomer (major)

¹³ C NMR(125MHz,CDCl ₃ ):δ19.4,19.7,21.5,22.1,28.4,32.5,34.4,38.4,38.6,82.5,112.6,142.7,169.9。

Acetic acid (1 sr,3 rs) -3-isopropyl-1-vinylcyclohexyl ester: cis-isomer (minor)

¹³ C NMR(125MHz,CDCl ₃ ):δ19.5,19.7,22.4,22.8,28.8,32.6,35.6,39.4,40.6,82.9,116.4,139.7,169.7。

4-isopropyl-1-vinylcyclohexyl acetate (10% in mixture, mixture of trans/cis isomers):

¹ H-NMR (500.15 MHz): 1.96 (s, 3H) characteristic signal.

Acetic acid 4-butyl-1-vinylcyclohexyl ester

The compound was prepared according to the general procedure and using (trans-4-butyl-1-vinylcyclohex-1-ol/cis-4-butyl-1-vinylcyclohex-1-ol) as starting alcohol.

GC crude product: 95.2% of 4-butyl-1-vinylcyclohexyl acetate is derived from 4-butyl-1-vinylcyclohex-1-ol (purity 95.2%).

Purity (GC) after purification was 97.0% (yield 86%, isomer mixture (trans/cis) of 61/36).

Trans-4-butyl-1-vinylcyclohexyl acetate/cis-4-butyl-1-vinylcyclohexyl acetate

¹ H-NMR (500.15 MHz): 0.83 (t, 2H, j=7.0 Hz), 0.89 (t, 1H, j=7.0 Hz) 1.02-1.40 (m, 10H), 1.57-1.73 (m, 3H), 1.46-1.57 (m, 3H), 1.96 major isomer (s, 2H), 2.02 minor isomer (s, 1H), 2.20-2.37 (m, 2H), 5.09 (d, 0.4H, j=11.1 Hz), 5.11 (d, 0.4H, j=17.6 Hz), 5.25 (d, 0.6H, j=10.6 Hz), 5.28 (d, 0.6H, j=17.4 Hz), 6.09 minor isomer (dd, 0.4H, j=17.6 Hz, j=11.1 Hz), 6.15 major isomer (dd, 0.6H, j=11.1 Hz).

¹³ C NMR(100MHz,CDCl ₃ ):δ14.11,14.13,22.09,22.32,22.94,22.96,28.17,28.97,29.18,29.47,34.54,34.57,35.31,36.05,36.65,36.69,81.66,82.27,112.85,115.93,139.89,142.42,169.82,169.97。

Acetic acid 2-ethyl-4, 4-dimethyl-1-vinylcyclohexyl ester

The compound was prepared according to the general procedure (THF as solvent) and using (1 sr,2 sr) -2-ethyl-4, 4-dimethyl-1-vinylcyclohex-1-ol/(1 sr,2 rs) -2-ethyl-4, 4-dimethyl-1-vinylcyclohex-1-ol as starting alcohol.

The reaction was carried out at 21% conversion (1 day). Unreacted starting material (2-ethyl-4, 4-dimethyl-1-vinylcyclohex-1-ol) is easily recovered by distillation or column chromatography.

The purity (GC) after purification was 95.7% ((isomer mixture (cis/trans) of 49.5/46.2).

(1 SR,2 SR) -2-ethyl-4, 4-dimethyl-1-vinylcyclohex-1-ol/(1 SR,2 RS) -2-ethyl-4, 4-dimethyl-1-vinylcyclohex-1-ol (mixture of cis/trans isomers)

¹ H-NMR (500.15 MHz) 0.79-0.88 (m, 3H), 0.93 (s, 1.5H), 0.94 (s, 3H), 1.02 (s, 1.5H) 1.06-1.47 (m, 4H), 1.57-1.72 (m, 2H), 1.48-1.59 (m, 2H), 2.02 major isomer (s, 1.5H), 2.03 minor isomer (s, 1.5H) 2.06-2.20 (m, 2H), 2.28-2.34 (m, 0.5H), 2.59-2.66 (m, 0.5H), 4.99 (d, 0.5H, j=17.7 Hz), 5.12 (d, 0.5H, j=11.3 Hz), 5.21 (dd, 0.5H, j=17.3 Hz, j=1.4 Hz), 5.24 (dd, 0.5H), 2.28-2.34 (m, 0.5H), 2.59-2.66 (m, 0.5H), 4.99 (d, 0.5H, j=17.7 Hz), 5.12 (d, j=11.3 Hz), 5.21 (dd, j=3.5 Hz).

¹³ C NMR(100MHz,CDCl ₃ ) Delta 12.12,12.18,21.90,21.92,22.27,22.60,24.7,25.26,28.68,29.90,30.31,30.90,32.47,33.01,34.20,36.58,39.66,41.46,41.67,44.92,84.92 (minor isomer), 86.65 (major isomer), 112.41,115.45,134.51,142.07,169.89 (major isomer), 170.11 (minor isomer).

Acetic acid 3-isopropyl-1-vinylcyclopentyl ester

The compound was prepared according to the general procedure and using (1 sr,3 rs) -3-isopropyl-1-vinylcyclopent-1-ol/(1 sr,3 sr) -3-isopropyl-1-vinylcyclopent-1-ol as starting alcohol.

GC crude product: 95.4% of acetic acid 3-isopropyl-1-vinylcyclopent-1-ol was derived from 3-isopropyl-1-vinylcyclopent-1-ol (purity 96.7%).

Purity (GC) after purification was 97.5% (yield 94.4%, mixture of cis/trans isomers): 59/39.

Acetic acid (1 SR,3 RS) -3-isopropyl-1-vinylcyclopentyl/acetic acid (1 SR,3 SR) -3-isopropyl-1-vinylcyclopentyl ester

¹ H-NMR (500.15 MHz) 0.88 major isomer (d, 3.6H, J=6.6 Hz), 0.89 minor isomer (d, 1.2H J =6.1 Hz), 0.90 minor isomerBody (d, 1.2H, j=6.1 Hz), 1.25-1.34 (m, 0.4H), 1.36-1.46 (m, 2H), 1.56-1.65 (m, 0.6H), 1.71-1.99 (m, 3H), 2.00 major isomer (s, 1.2H), 2.01 minor isomer (s, 1.8H), 2.06-2.12 (m, 1H), 2.20-2.25 (m, 0.6H), 2.29-2.34 (m, 0.4H), 5.07 (d, 0.4H, j=10.6 Hz), 5.08 (d, 0.6H, j=11.0 Hz), 5.11 (d, 0.4H, j=18.1 Hz), 5.12 (d, 0.6H, j=17.6 Hz), 6.12 (dd, 0.6H, j=17.34 (m, 0.4H), 5.07 (d, j=10.8 Hz), 5.07 (j=10.8 Hz).

Major isomer (cis)

¹³ C NMR(125MHz,CDCl ₃ ):δ21.12,21.29,22.05,28.51,33.64,37.79,42.61,45.38,89.64,112.76,141.04,170.15。

Minor isomer (trans)

¹³ C NMR(125MHz,CDCl ₃ ):δ21.28,21.33,22.13,28.55,33.53,37.56,42.84,45.38,90.71,112.64,140.86,170.22。

c) Preparation of ((4, 4-dimethyl-1-vinylcyclohexyl) oxy) trimethylsilane compound of formula (II)

At N ₂ To a stirred solution of 4, 4-dimethyl-1-vinyl-cyclohexanol (30 g, purity 95.9%,186.5 mmol) obtained in example 1 a) in dichloromethane (750 mL) was added triethylamine (56.62 g,559.6mmol,3 eq.) and chlorotrimethylsilane (28.37 g,261.1mmol,1.4 eq.) under water cooling. After 22 hours at room temperature, complete conversion of the starting material was observed. Slowly add saturated NaHCO ₃ Aqueous (750 mL) and the organic phase separated. The aqueous phase was extracted twice with 500mL diethyl ether and 250mL dichloromethane. The combined organic phases were washed with saturated aqueous NaCl solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure (40 ℃ C., 500-4.8 mbar). The crude product (44.8 g, 96.1% pure) was filtered off as a red solid (crude product 40.9 g).

The crude product was purified by distillation (Vigreux) at 0.2-0.099 mbar, boiling point 32.6-36.7 ℃, pot 70 ℃, cup 83 ℃). The ((4, 4-dimethyl-1-vinylcyclohexyl) oxy) trimethylsilane was isolated in 94.5% yield (40.0 g, 99.8% purity, 176.3 mmol).

¹ H-NMR(500.15MHz):0.09(s,9H),0.86(s,3H),0.93(s,3H),1.14-1.12(m,2H),1.46-1.63(m,6H),5.03(d,1H,J＝10.8Hz),5.15(d,1H,J＝17.6Hz),5.95(1H,dd,J＝17.7Hz,J＝10.8Hz)。

¹³ C NMR(125MHz,CDCl ₃ ):δ2.6,26.3,29.5,33.5,34.0,35.1,74.3,112.2,145.8。

Example 22

Preparation of different compounds of formula (I)

a) Preparation of 3- (4- (tert-butyl) cyclohex-1-en-1-yl) propanal

Step 1: hydrogenated methyl (4-tert-butyl-1-vinyl-cyclohexyl) acetate using biphenphos-Rh Acylation

The autoclave was charged with acetic acid (4-t-butyl-1-vinyl-cyclohexyl) ester (trans/cis ratio: 54.5%/44.5%,5.06g,22.56 mmol), rh (CO) ₂ acac (3.2 mg,0.0124 mmol) and biphospos (26.8 mg,0.034 mmol). By H ₂ The vessel was purged with/CO (1:1, 4X5 bar) and heated under vigorous stirring at 90℃and 10 bar synthesis gas pressure for 24 hours. After cooling and depressurization, GLC analysis of the semi-crystalline crude product (DB-1, 10 m, 100. Mu.m, 80 ℃,1 min; 40 DEG/min to 240 ℃ C.; 5 min or DB-WAX,10 m, 100. Mu.m, 80 ℃,1 min; 40 DEG/min to 240 ℃ C.; 5 min) shows the total conversion and the presence of 4- (tert-butyl) -1- (3-oxopropyl) cyclohexyl acetate (92.2%; trans/cis ratio: 54.4%/37.8%).

Cis-4- (tert-butyl) -1- (3-oxopropyl) cyclohexyl acetate:

¹ H-NMR(600.15MHz):δ0.85(s,9H,4-(C(CH ₃ ) ₃ ),1.14-1.24(m,4H),1.55-1.66(m,3H),2.02(s,3H,COCH ₃ ),2.21(t,2H)2.33-2.37(m,2H,H-1’),2.43(t,2H,H-2’),9.74(t,1H, ² J _1,2 ＝1.54Hz,H-1)。

¹³ C NMR(125MHz,CDCl ₃ ):δ22.1(q),22.2(t),27.4(q),30.4(t),32.3(s),34.8(t),38.3(t),47.2(d),82.2(s),170.4(s),202.0(d)。

trans-4- (tert-butyl) -1- (3-oxopropyl) cyclohexyl acetate:

¹ H-NMR(600.15MHz):δ0.85(s,9H,4-(C(CH ₃ ) ₃ ),1.06-1.16(m,3H),1.67-1.77(m,4H),1.97(s,3H,COCH ₃ ),2.13-2.19(m,2H,),2.27-2.32(m,2H,H-1’),2.40-2.46(m,2H,H-2’),9.78(t,1H, ² J _1,2 ＝1.60Hz,H-1’)。

¹³ C NMR(100MHz,CDCl ₃ ):δ22.4(q),23.9(t),24.8(t),27.6(q),32.2(s),34.6(t),38.3(t),47.3(d),84.2(s),170.3(s),202.0(d)。

step 2: trans-1- (2- (1, 3-dioxolan-2-yl) ethyl) -4- (tert-butyl) cyclohexyl acetate/ethyl acetate Preparation of the acid cis-1- (2- (1, 3-dioxolan-2-yl) ethyl) -4- (tert-butyl) cyclohexyl ester

This compound was prepared according to the procedure reported in example 10 using the compound prepared in the previous step as starting material.

GC crude product: 52.0%/30.6% of 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4- (tert-butyl) cyclohexyl acetate from 4- (tert-butyl) -1- (3-oxopropyl) cyclohexyl acetate (54.4%/37.8%).

The purity (GC) after purification was 55.2%/38.3%. The product contained 2.6% 4- (tert-butyl) -1- (3-oxopropyl) cyclohexyl acetate and 3.9% trans-4- (tert-butyl) -1- (3-oxopropyl) cyclohexyl acetate.

Acetic acid 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4- (tert-butyl) cyclohexyl ester

¹ H-NMR (500.15 MHz) 0.85 (s, 9H), 0.97-1.27 (m, 4H,1.55-1.72 (m, 6H), 1.92 (trans isomer) and 2.00 (cis isomer) (s, 3H), 2.04-2.10 (m, 1H), 2.18-2.27 (m, 1H), 2.33-2.45 (m, 1H), 3.80-3.87 (m, 2H), 3.94-4.00 (m, 2H), 4.82 (cis isomer) and 4.85 (trans isomer) (t, 1H, J=4.8 Hz).

Trans isomer (major)

¹³ C NMR(125MHz,CDCl ₃ ):δ22.5,23.9,26.3,27.6,27.7,32.2,34.9,47.4,64.9,84.6,104.6,170.3。

Cis-isomer (minor)

¹³ C NMR(125MHz,CDCl ₃ ):δ22.1,22.3,27.5,27.9,32.4,32.5,34.8,47.3,64.9,82.7,104.6,170.3。

Step 3: preparation of 2- (2- (4- (tert-butyl) cyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane

To a solution of dioxolane acetate (3.126 mmol) prepared in the previous step in 5mL of anhydrous toluene was added 0.15 equivalent of BF ₃ ·Et ₂ O. The mixture was stirred at room temperature for 30 min (complete conversion of starting material) and then added to 20mL of saturated NaHCO ₃ In an aqueous solution. When gas formation is no longer observed, 15mL of MTBE is added and the mixture is stirred for 10 minutes. The organic phase was separated and washed with water and saturated aqueous NaCl solution. With Na ₂ SO ₄ After drying, the solvent is evaporated under reduced pressure (500-50 mbar,50 ℃). The crude product was purified by flash chromatography.

GC crude product: 91.8% of 2- (2- (4- (tert-butyl) cyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane/3.7% of 2- (2- (4- (tert-butyl) cyclohexylidene) ethyl) -1, 3-dioxolane from 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4- (tert-butyl) cyclohexyl acetate (purity 93.5%).

The purity (GC) after purification was 94.0%/3.5%.

2- (2- (4- (tert-butyl) cyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane

¹ H-NMR(500.15MHz):0.86(s,9H),1.10-1.26(m,2H),1.71-1.84(m,4H),1.94-2.08(m,5H),3.82-3.89(m,2H),3.93-4.00(m,2H),4.85(t,1H,J＝4.9Hz),5.40-5.44(m,1H)。

¹³ C NMR(90MHz,CDCl ₃ ):δ24.3,26.8,27.2,29.9,31.7,32.2,32.2,44.2,64.8,104.4,121.2,136.7。

Step 4: preparation of 3- (4- (tert-butyl) cyclohex-1-en-1-yl) propanal

This compound was prepared according to the procedure reported in example 13 using the compound prepared in the previous step as starting material.

CDCl ₃ In (a) and (b) ¹ H and ¹³ the results of the C-NMR analysis are consistent with literature data (see EP105405 to B.winter)3A2)。

3- (4- (tert-butyl) cyclohex-1-en-1-yl) propanal

¹³ C NMR(90MHz,CDCl ₃ ):δ24.1,26.8,27.2,29.7,29.9,32.2,41.9,44.0,122.1,135.5,202.8。

b) Preparation of 3- (5-isopropylcyclohex-1-en-1-yl) propanal/3- (3-isopropylcyclohex-1-en-1-yl) propanal

Step 1: hydrogenated methyl acetate (3-isopropyl-1-vinyl-cyclohexyl) using biphenphos-Rh Acylation

The autoclave was charged with a mixture (5.04 g,23.965 mmol) of 3-isopropyl-1-vinyl-cyclohexyl acetate (1 SR,3RS/1SR,3SR, 42%/47%) and 4-isopropyl-1-vinyl-cyclohexyl acetate (cis/trans, 4%/6.5%) of Rh (CO) ₂ acac (2.5 mg,0.0119 mmol) and biphospos (28.7 mg,0.0365 mmol). By H ₂ The vessel was purged with/CO (1:1, 4X5 bar) and heated under vigorous stirring at 90℃and 10 bar synthesis gas pressure for 24 hours. After cooling and depressurization, GLC analysis of the crude colorless oil showed complete conversion and presence of linear 3-isopropyl-1- (3-oxopropyl) cyclohexyl acetate (1 SR,3SR/1SR,3RS, 39.7%/45.3%) and 4-isopropyl-1- (3-oxopropyl) cyclohexyl acetate (cis/trans, 4%/6.3%).

Acetic acid 1SR,3SR/1SR,3 RS-3-isopropyl-1- (3-oxopropyl) cyclohexyl ester

¹ H-NMR(500.15MHz):δ0.83-0.88(m,6H),0.89-1.01(m,1H),1.04-1.51(m,4H),1.57-1.79(m,3H),1.95-2.03(2x s,3H,COCH ₃ ),2.04-2.14(m,1H),2.17-2.37(m,3H),2.41-2.47(m,2H),9.78(t, ² J _1,2 ＝1.60Hz,),9.75(t, ² J _1,2 =1.76 Hz,) the two aldehyde proton signals together are 1H.

¹³ C NMR(125MHz,CDCl ₃ ):δ19.4(q),19.6(q),19.74(q),19.75(q),21.5(t),22.2(q),22.5(q),22.7(t),25.6(t),28.5(t),28.7(t),30.9(t),32.4(d),32.7(d),34.4(t),34.5(t),37.9(t),38.0(t),38.2(t),38.3(t),38.6(d),40.6(d),83.4(s),85.1(s),170.27(s),170.33(s),201.93(s),201.96(s)。

Step 2: preparation of 1- (2- (1, 3-dioxolan-2-yl) ethyl) -3-isopropylcyclohexyl acetate

GC crude product: 40.5%/46.1% 1- (2- (1, 3-dioxolan-2-yl) ethyl) -3-isopropyl cyclohexyl acetate and 2.7% 2- (2- (5-isopropyl cyclohex-1-en-1-yl) ethyl) -1, 3-dioxolan from 3-isopropyl-1- (3-oxopropyl) cyclohexyl acetate (39.7%/45.3%).

The purity (GC) after purification was 41.9%/47.4% (product containing 10% 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4-isopropylcyclohexyl acetate, trans/cis isomer mixture).

(1 SR,3 RS) -1- (2- (1, 3-dioxan-2-yl) ethyl) -3-isopropylcyclohexyl acetate (major isomer)

(1 SR,3 SR) -1- (2- (1, 3-dioxolan-2-yl) ethyl) -3-isopropylcyclohexyl acetate (minor isomer)

¹ H-NMR (500.15 MHz): 0.83-0.86 (m, 6H), 0.89-1.49 (m, 5H), 1.54-1.74 (m, 5H), 1.87 (cis-isomer) and 2.00 (trans-isomer) (s, 3H), 1.98-2.19 (m, 3H), 2.28-2.37 (m, 1H), 3.81-3.88 (m, 2H), 3.93-4.00 (m, 2H), 4.83 (cis-isomer) and 4.85 (trans-isomer) (t, 1H, J=4.8 Hz).

¹³ C NMR(100MHz,CDCl ₃ ):δ19.37,19.64,19.74,19.76,21.58,22.20,22.54,22.71,27.12,27.65,27.83,28.59,28.78,32.47,32.69,32.96,34.46,34.65,38.07,38.13,38.62,40.51,64.90(2C),83.82,85.52,104.58,104.62,170.23,170.27。

Acetic acid 1- (2- (1, 3-dioxan-2-yl) ethyl) -4-isopropylcyclohexyl ester (characteristic signal, trans/cis isomer mixture)

¹³ C NMR(100MHz,CDCl ₃ ) Delta 19.85,20.18,22.14,22.45,24.81,26.05,26.99,27.68,27.86,31.69,32.50,34.07,34.53,43.00 (major isomer), 43.31 (minor isomer), 64.90,82.89 (minor isomer), 84.58 (major isomer), 104.56,104.60,170.30,170.33.

Step 3:2- (2- (5-Isopropylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxalane/2- (2- (3-iso) ethyl) Preparation of propylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane

This compound was prepared according to the procedure reported for the preparation of 2- (2- (4- (tert-butyl) cyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane using the compound prepared in the previous step as starting material.

GC crude product: 55.8% of 2- (2- (5-isopropylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane, 23.9% of 2- (2- (3-isopropylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane, 7.2% of 2- (2- (3-isopropylcyclohexylidene) ethyl) -1, 3-dioxolane, from acetic acid 1- (2- (1, 3-dioxolan-2-yl) ethyl) -3-isopropylcyclohexyl ester 41.9%/47.4%.

The purity (GC) after purification was 57.2%/24.7%/7.3% (the product contained 10% 2- (2- (4-isopropylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane).

2- (2- (5-Isopropylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane (major isomer)/2- (2- (3-Isopropylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane (minor isomer)

¹ H-NMR (500.15 MHz) 0.82-0.92 (m, 6H), 1.06-1.35 (m, 2H), 1.39-1.59 (m, 1H), 1.63-2.10 (m, 9H), 3.81-3.90 (m, 2H), 3.91-4.00 (m, 2H), 4.85 (minor isomer) and 4.86 (major isomer) (t, 1H, J=4.8 Hz), 5.34 (m, 0.3H), 5.41 (m, 0.7H).

2- (2- (5-Isopropylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxacyclopentane (the major isomer)

¹³ C NMR(125MHz,CDCl ₃ ):δ19.6,19.9,25.9,26.0,32.1,32.2,32.2,32.4,40.5,64.9,104.5,120.8,136.8。

2- (2- (3-Isopropylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxacyclopentane (minor isomer)

¹³ C NMR(125MHz,CDCl ₃ ):δ19.3,19.6,22.6,25.4,28.7,32.2,32.3,32.4,41.8,64.9,104.4,124.9,137.2。

2- (2- (4-isopropylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane (10% of the mixture).

¹³ C NMR(100MHz,CDCl ₃ ):δ19.7,20.0,26.4,28.9,29.1,31.8,32.2,32.3,40.2,64.8,104.6,120.9,136.7。

Step 4:3- (5-Isopropylcyclohex-1-en-1-yl) propanal/3- (3-Isopropylcyclohex-1-en-1-yl) propanal +. Preparation of 3- (4-butylcyclohex-1-en-1-yl) propanal

The compound (7/3 mixture) was prepared according to the procedure reported in example 13 using the compound prepared in the previous step as starting material. In CDCl3 ¹ H and ¹³ the results of the C-NMR analysis are consistent with literature data (see WO2017046071A1 of R.Moretti, A.Birkbeck).

3- (5-Isopropylcyclohex-1-en-1-yl) propanal (major isomer)

¹³ C NMR(125MHz,CDCl ₃ ):δ19.6,19.9,25.8,25.9,30.1,32.3,32.3,40.4,41.9,121.7,135.6,202.8。

3- (3-Isopropylcyclohex-1-en-1-yl) propanal (minor isomer)

¹³ C NMR(125MHz,CDCl ₃ ):δ19.3,19.7,22.4,25.2,28.7,30.4,32.3,41.8,42.0,125.8,136.1,202.8。

3- (4-Isopropylcyclohex-1-en-1-yl) propanal (10% in mixture)

CDCl ₃ The NMR analysis results in (B) are consistent with literature data (E.Singer, B, holscher, U.S. Pat. No. 5,2013/90390,2013, A1).

¹³ C NMR(90MHz,CDCl ₃ ):δ19.7,19.9,26.3,28.9,29.2,29.8,32.2,40.0,41.9,121.8,135.6,202.8。

c) Preparation of 3- (4-butylcyclohex-1-en-1-yl) propanal

Step 1: hydroformylation of acetic acid (4-butyl-1-vinylcyclohexyl ester) using biphenphos-Rh

The autoclave was charged with acetic acid (4-butyl-1-vinyl-cyclohexyl) ester (cis/trans, 36%/61%,5.06g, 22.55mmol), rh (CO) ₂ A mixture of acac (3.1 mg,0.012 mmol) and BiPhePhos (26.3 mg,0.0334 mmol). By H ₂ The vessel was purged with/CO (1:1, 4X5 bar) and heated under vigorous stirring at 90℃and 10 bar synthesis gas pressure for 24 hours. After cooling and depressurization, GLC analysis of the crude colorless oil showed complete conversion and presence of linear 4-butyl-1- (3-oxopropyl) cyclohexyl acetate (89.9%, cis/trans, 33.2%/56.7%).

4-butyl-1- (3-oxopropyl) cyclohexyl acetate:

¹ H-NMR(500.15MHz):δ0.85-0.92(m,3H),1.03-1.14(m,2H),1.15-1.40(m,8H),1.55-1.62(m,1H),1.64-1.72(m,1H),1.77-1.84(m,1H),1.93-1.97(m,1H),1.98,2.02(2x s,3H,COCH ₃ ),2.20-2.25(m,1H),2.27-2.34(m,2H),2.40-2.46(m,2H),9.77(t,1H, ² J _1,2 ＝1.60Hz,H-1),9.75(t,1H, ² J _1,2 =1.76 hz, H-1) the two aldehyde proton signals together are 1H.

¹³ C NMR(125MHz,CDCl ₃ ):δ14.10,14.11(q),22.12,22.42(q),22.92,22.95(t).25.92(t),28.1,28.75(t),29.15,29.46(t),30.45,33.32,34.38,35.16(t),35.87(d),36.66(t),36.80(d),38.25,38.29(t),82.56,84.17(s),170.35,170.4(s),201.95,201.98(s)。

Step 2: preparation of 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4-butylcyclohexyl acetate

GC crude product: 50.1%/31.7% of 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4-butylcyclohexyl acetate and 4.3% of 2- (2- (4-butylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolan/1.8% of 2- (2- (4-butylcyclohexylidene) ethyl) -1, 3-dioxolan from 4-butyl-1- (3-oxopropyl) cyclohexyl acetate (33.2%/56.7%).

Purity (GC) after purification was 33.8%/66.2%.

(2- (4- (tert-butyl) cyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane

¹ H-NMR (500.15 MHz): 0.88 and 0.89 (t, 3H, j=7.0 Hz), 1.03-1.14 (m, 2H), 1.15-1.38 (m, 8H), 1.53-1.78 (m, 6H), 1.97 (trans isomer) and 2.00 (cis isomer) (s, 3H), 1.99-2.09 (m, 2.4H), 2.30-2.36 (m, 0.6H), 3.81-3.88 (m 2H), 3.93-4.00 (m, 2H), 4.82 (cis isomer) and 4.84 (trans isomer) (t, 1H, j=4.8 Hz).

Trans of major isomer

¹³ C NMR(125MHz,CDCl ₃ ):δ14.1,22.4,22.9,27.7,28.2,28.8,29.5,33.5,34.4,35.9,64.9,84.5,104.6,170.3。

Minor isomer cis

¹³ C NMR(125MHz,CDCl ₃ ):δ14.1,22.2,23.0,27.6,27.9,29.2,32.5,35.2,36.7,36.9,64.9,83.0,104.6,170.3。

Step 3: preparation of 2- (2- (4-butylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane

GC crude product: 91.2% of 2- (2- (4-butylcyclohexyl-1-en-1-yl) ethyl) -1, 3-dioxolane/5.2% of 2- (2- (4-butylcyclohexylidene) ethyl) -1, 3-dioxolane from 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4-butylcyclohexyl acetate (purity 33.8%/66.2%).

Purity (GC) after purification was 92.9%/5.8%.

2- (2- (4-butylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane

¹ H-NMR(500.15MHz):0.89(t,3H,J＝7.0Hz),1.14-1.34(m,7H),1.39-1.40(m,1H),1.55-1.65(m,1H),1.70-1.79(m,3H),1.89-2.12(m,5H),3.82-3.89(m,2H),3.92-4.01(m,2H),4.85(t,1H,J＝4.8Hz),5.38-5.42(m,1H)。

¹³ C NMR(125MHz,CDCl ₃ ):δ14.2,23.0,28.5,29.3,29.4,31.9,32.1,32.2,33.5,36.2,64.9,104.5,120.6,136.8。

Step 4:3- (4-butylcyclohex-1-ene)Preparation of 1-yl) propanal

This compound was prepared according to the procedure reported in example 13 using the compound prepared in the previous step as starting material. CDCl ₃ A kind of electronic device ¹ H and ¹³ the results of the C-NMR analysis are consistent with literature data (see WO2019185599A1 to R.Moretti).

3- (4-butylcyclohex-1-en-1-yl) propanal

¹³ C NMR(125MHz,CDCl ₃ ):δ14.1,23.0,28.6,29.2,29.2,29.9,32.0,33.4,36.1,41.9,121.5,135.6,202.8。

d) Preparation of 3- (2-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) propanal/3- (6-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) propanal

Step 1: addition of 2-ethyl-4, 4-dimethyl-1-vinyl-cyclohexyl acetate using biphenhos-Rh Hydroformylation process

The autoclave was charged with a mixture of acetic acid (1 SR,2 SR) -and (1 SR,2 RS) -2-ethyl-4, 4-dimethyl-1-vinyl-cyclohexyl ester (49.5%/46.2%, 3.02g, 13.463mmol), rh (CO) ₂ acac (2.1 mg,0.0081 mmol) and biphospos (16.8 mg,0.0214 mmol). By H ₂ The vessel was purged with/CO (1:1, 4X5 bar) and heated under vigorous stirring at 90℃and 10 bar synthesis gas pressure for 24 hours. After cooling and depressurization, GLC analysis of the crude yellow oil showed complete conversion and presence of linear acetic acid (1 SR,2 SR) -and (1 SR,2 RS) -2-ethyl-4, 4-dimethyl-1- (3-oxopropyl) cyclohexyl ester (49%/42%).

(1 sr,2 sr) -and (1 sr,2 rs) -2-ethyl-4, 4-dimethyl-1- (3-oxopropyl) cyclohexyl acetate:

¹ H-NMR(500.15MHz):δ0.82-1.06(m,11H),1.11-1.25(m,2H),1.26-1.38(m,1H),1.40-1.62(m,2H),1.62-1.67(dt,1H),1.91-2.09(m,4H),2.37-2.73(m,4H),9.78(t,1H, ² J _1,2 ＝1.60Hz,H-1),9.75(t,1H, ² J _1,2 =1.76 Hz,) the two aldehyde proton signals together are 1H.

¹³ C NMR(125MHz,CDCl ₃ ):δ11.97,12.29(q),21.23,21.87(t),22.11(q),22.53(t),22.67,24.74,25.70(q),27.14,27.85,28.00(t),29.82,30.45(s),32.28,32.91,34.39,36.32,38.37,39.20(t),39.48,41.14(d),41.95(t),85.28,88.31,170.28,170.56(s),201.52,202.39(d)。

Step 2: acetic acid 1- (2- (1, 3-dioxolan-2-yl) ethyl) -2-ethyl-4, 4-dimethylcyclohexyl ester Preparation

GC crude product: 44.1%/38.4% acetic acid 1- (2- (1, 3-dioxolan-2-yl) ethyl) -2-ethyl-4, 4-dimethylcyclohexyl and 2- (2- (2-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolan/2- (2- (6-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolan (5.6%/2.6%) 49%/42% from acetic acid 2-ethyl-4, 4-dimethyl-1- (3-oxopropyl) cyclohexyl.

The purity (GC) after purification was 51.9%/45.3% (2.7% 2-ethyl-4, 4-dimethyl-1- (3-oxopropyl) cyclohexyl acetate).

Acetic acid 1- (2- (1, 3-dioxolan-2-yl) ethyl) -2-ethyl-4, 4-dimethylcyclohexyl ester

¹ H-NMR (500.15 MHz) 0.85 major isomer (t, 1.5H, J=7.3 Hz), 0.86 minor isomer (t, 1.5H, J=7.5 Hz), 0.88 (s, 1.5H), 0.91 (s, 3H), 0.93-1.00 (m, 1H), 1.02 (s, 1.5H), 1.10-1.37 (m, 4H), 1.43-1.73 (m, 5H), 1.78-1.90 (m, 1H), 1.97 (s, 3H), 2.44-2.69 (m, 2H), 3.82-3.91 (m, 2H), 3.93-4.02 (m, 2H), 4.83 major isomer (t, 0.5H, J=4.6 Hz), 4.85 minor isomer (t, 0.5H, J=4.2 Hz).

(1 SR,2 SR) -1- (2- (1, 3-dioxolan-2-yl) ethyl) -2-ethyl-4, 4-dimethylcyclohexyl acetate (major isomer)

¹³ C NMR(125MHz,CDCl ₃ ):δ12.3,21.9,22.8,24.4,24.7,27.7,29.8,30.4,33.0,34.5,39.1,39.5,64.9,88.7,104.9,170.6。

(1 SR,2 RS) -1- (2- (1, 3-dioxolan-2-yl) ethyl) -2-ethyl-4, 4-dimethylcyclohexyl acetate (minor isomer)

¹³ C NMR(125MHz,CDCl ₃ ):δ11.9,21.1,22.2,25.9,27.1,27.7,29.2,29.9,32.3,36.3,40.2,41.9,64.9,86.1,104.5,170.4。

Step 3:2- (2- (2-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxacyclopentane/2-) Preparation of (2- (6-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane

GC crude product: 71.9%/13.8% of 2- (2- (2-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane/2- (2- (6-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane and 2.9% of 2- (2- (2-ethyl-4, 4-dimethylcyclohexylidene) ethyl) -1, 3-dioxolane from acetic acid 1- (2- (1, 3-dioxan-2-yl) ethyl) -2-ethyl-4, 4-dimethylcyclohexanecarbonate (purity 51.9%/45.3%).

Purity (GC) after purification was 81.8%/15.4%/2.7%.

2- (2- (2-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane/2- (2- (6-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane

¹ H-NMR (500.15 MHz): 0.83 minor isomer (t, 0.5H, j=7.4 Hz), 0.86 major isomer (s, 5H), 0.92 major isomer (t, 2.5H, j=7.5 Hz), 0.93 minor isomer (s, 1H), 1.31 major isomer (t, 1.7H, j=6.5 Hz), 1.39-1.45 (m, 0.15H), 1.59-1.73 (m, 4.3H), 1.75-1.87 (m, 0.3H), 1.93-2.01 (m, 3.4H), 2.11 (t, 2H, j=8.5 Hz), 3.81-3.89 (m, 2H), 3.93-4.01 (m, 2H), 4.83 major isomer (t, 0.85H, j=4.6 Hz), 4.86 isomer (t, 0.15H), 1.75-1.87 (m, 0.3H), 1.93-2.01 (m, 2.5 Hz), 4.42H).

2- (2- (2-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxacyclopentane (the major isomer)

¹³ C NMR(125MHz,CDCl ₃ ):δ13.0,26.0,26.9,27.2,28.1,28.1,29.0,32.9,35.9,43.0,64.9,104.5,126.8,131.4。

2- (2- (6-Ethyl-4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxacyclopentane (minor isomer)

¹³ C NMR(125MHz,CDCl ₃ ):δ10.4,24.9,25.0,28.9,29.2,31.9,32.5,35.5,39.5,41.5,64.9,104.5,121.7,138.2。

Step 4:3- (2-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) propanal and 3- (6-ethyl-4, 4-dimethylcyclo) Hex-1-en-1-yl) propanal preparation

The compound (mixture of 84/16) was prepared according to the procedure reported in example 13 using the compound prepared in the previous step as starting material.

3- (2-ethyl-4, 4-dimethylcyclohex-1-en-1-yl) propanal (major isomer)

¹³ C NMR(125MHz,CDCl ₃ ):δ13.0,25.1,26.1,27.0,28.1,29.0,35.8,43.0,43.1,125.5,132.6,202.8。

3- (6-Ethyl-4, 4-dimethylcyclohex-1-en-1-yl) propanal (minor isomer)

C NMR(125MHz,CDCl ₃ ):δ10.2,24.9,24.9,27.0,29.2,32.0,35.7,39.4,41.4,122.7,137.0,202.8。

e) Preparation of 3- (4-isopropylcyclopent-1-en-1-yl) propanal/3- (3-isopropylcyclopent-1-en-1-yl) propanal

Step 1: hydroformylation of 3-isopropyl-1-vinylcyclopentylacetate using biphenphos-Rh

The autoclave was charged with a mixture of acetic acid (1 SR,3 RS) -and (1 SR,3 SR) - (3-isopropyl-1-vinyl-cyclopentyl) ester (59%/39%, 5.02g,25.574 mmol), [ Rh (CO) ₂ acac](3.3 mg,0.0128 mmol) and BiPhePhos (30.7 mg,0.039 mmol). By H ₂ The vessel was purged with/CO (1:1, 4X5 bar) and heated under vigorous stirring at 90℃and 10 bar synthesis gas pressure for 24 hours. After cooling and depressurization, GLC analysis of the crude yellow oil showed total conversion and presence of linear acetic acid (1 SR,3 SR) -and (1 SR,3 RS) -3-isopropyl-1- (3-oxopropyl) cyclopentyl ester (57%/35%).

Acetic acid (1 sr,3 sr) -and (1 sr,3 rs) -3-isopropyl-1- (3-oxopropyl) cyclopent-late:

¹ H-NMR(500.15MHz):δ0.86-0.90(m,6H),1.14-1.25(m,1H),1.33-1.46(m,1H),1.50-1.63(m,1H),1.70-1.89(m,3H),1.97-2.00(2x s,3H,COCH3),2.00-2.32(m,3H),2.33-2.42(m,1H),2.42-2.48(m,2H),9.75(m,1H)。

(1 SR,3 SR) -3-isopropyl-1- (3-oxopropyl) cyclopentylacetate (major)

¹³ C NMR(125MHz,CDCl ₃ ):δ21.2(q),21.4(q),22.1(q),28.9(t),30.2(t),33.5(d),37.7(t),39.4(t),42.6(t),46.2(d),91.0(s),170.5(s),201.9(d)。

(1 SR,3 RS) -3-isopropyl-1- (3-oxopropyl) cyclopentylacetate (minor)

¹³ C NMR(125MHz,CDCl ₃ ):δ21.2(q),21.4(q),22.2(q),29.0(t),30.1(t),33.5(d),37.4(t),39.5(t),42.7(t),45.6(d),91.7(s),170.6(s),201.8(d)。

Step 2: preparation of 1- (2- (1, 3-dioxolan-2-yl) ethyl) -3-isopropylcyclopent acetate

GC crude product: 38.2%/27.6% 1- (2- (1, 3-dioxolan-2-yl) ethyl) -3-isopropylcyclopent-ate and 7.3%/6.0 of 2- (2- (4-isopropylcyclopent-1-en-1-yl) ethyl) -1, 3-dioxolan/2- (2- (3-isopropylcyclopent-1-en-1-yl) ethyl) -1, 3-dioxolan from 3-isopropyl-1- (3-oxopropyl) cyclopent-ate acetate (57%/35%).

The purity (GC) after purification was 57.4%/41.6%.

Acetic acid 1- (2- (1, 3-dioxolan-2-yl) ethyl) -3-isopropylcyclopent-late

¹ H-NMR (500.15 MHz) 0.85-0.89 (m, 6H), 1.15-1.44 (m, 2H), 1.48-1.88 (m, 6H), 1.88-1.98 (m, 1H), 1.97 (major isomer) and 1.98 (minor isomer) (s, 3H), 2.04-2.18 (m, 2.6H), 2.25-2.32 (m, 0.4H), 3.80-3.88 (m, 2H), 3.92-4.00 (m, 2H), 4.83 (t, J=4.8 Hz,1H)。

(1 SR,3 SR) -1- (2- (1, 3-dioxolan-2-yl) ethyl) -3-isopropylcyclopent-yl acetate (major isomer)

¹³ C NMR(125MHz,CDCl ₃ ):δ21.2,21.4,22.2,28.9,29.0,31.9,33.6,37.7,42.8,46.3,64.9,91.5,104.4,170.4。

(1 SR,3 RS) -1- (2- (1, 3-dioxan-2-yl) ethyl) -3-isopropylcyclopent-yl acetate (minor isomer)

¹³ C NMR(125MHz,CDCl ₃ ):δ21.3,21.4,22.2,29.1,29.1,31.9,33.5,37.5,42.7,45.7,64.9,92.2,104.4,170.4。

Step 3:2- (2- (4-isopropylcyclopent-1-en-1-yl) ethyl) -1, 3-dioxolane/2- (2- (3-iso-f- Preparation of propylcyclopent-1-en-1-yl) ethyl) -1, 3-dioxolane

GC crude product: 42.9%/40.2% 2- (2- (4-isopropylcyclopent-1-en-1-yl) ethyl) -1, 3-dioxolane/2- (2- (3-isopropylcyclopent-1-en-1-yl) ethyl) -1, 3-dioxolane and 7.3% 2- (2- (3-isopropylcyclopentylene) ethyl) -1, 3-dioxolane from acetic acid 1- (2- (1, 3-dioxolan-2-yl) ethyl) -3-isopropylcyclopent-ate (purity 57.4%/41.6%).

Purity (GC) after purification was 47.8%/47.6%/4.6%.

2- (2- (4-isopropylcyclopent-1-en-1-yl) ethyl) -1, 3-dioxolane/2- (2- (3-isopropylcyclopent-1-en-1-yl) ethyl) -1, 3-dioxolane

¹ H-NMR(500.15MHz):0.83,0.86,0.87,0.87(d,6H,J＝6.7Hz),1.42-1.54(m,1.5H)1.77-1.84(m,2H),1.92-2.02(m,2H),2.12-2.45(m,4.5H),3.82-3.89(m,2H),3.93-4.01(m,2H),4.87(t,J＝4.8Hz,0.5H),4.88(t,J＝4.8Hz,0.5H),5.29-5.32(m,0.5H),5.33-5.35(m,0.5H)。

¹³ C NMR(125MHz,CDCl ₃ ):δ20.3,20.5,20.9,21.0,25.7,25.8,27.8,32.1,32.3,33.0,33.6,34.9,36.9,39.6,46.2,52.8,64.9,64.9,104.3,104.3,123.0,126.6,143.2,143.9。

Characteristic signal of 2- (2- (4-isopropylcyclopent-1-en-1-yl) ethyl) -1, 3-dioxolane: ¹³ C NMR(125MHz,CDCl ₃ )：46.2ppm

characteristic signal of 2- (2- (3-isopropylcyclopent-1-en-1-yl) ethyl) -1, 3-dioxolane: ¹³ C NMR(125MHz,CDCl ₃ )：52.8ppm

step 4:3- (4-isopropylcyclopent-1-en-1-yl) propanal/3- (3-isopropylcyclopent-1-en-1-yl) propanal Preparation

The compound (1/1 mixture) was prepared according to the procedure reported in example 13 using the compound prepared in the previous step as starting material.

¹ H-NMR(500.15MHz):0.83,0.86,0.86,0.87(d,6H,J＝6.7Hz),1.43-1.54(m,1.5H)1.94-2.03(m,2H),2.18-2.45(m,4.5H),2.54-2.60(m,2H),5.28-5.31(m,0.5H),5.32-5.34(m,0.5H),9.75(t,0.5H,J＝1.86Hz),9.77(t,0.5H,J＝1.74Hz)。

3- (4-isopropylcyclopent-1-en-1-yl) propanal

¹³ C NMR(150MHz,CDCl ₃ ):δ20.9,21.0,23.9,33.5,36.9,39.7,41.8,46.1,124.0,142.0,202.6。

3- (3-isopropylcyclopent-1-en-1-yl) propanal

¹³ C NMR(150MHz,CDCl ₃ ):δ20.2,20.5,23.8,27.7,32.9,35.0,42.0,52.8,127.5,142.7,202.6。

Example 23

Addition of ((4, 4-dimethyl-1-vinylcyclohexyl) oxy) trimethylsilane using BIPHEPHOS-Rh Hydroformylation process

The autoclave was charged with (4, 4-dimethyl-1-vinyl-cyclohexyloxy) -trimethyl-silane (96%, 5.04g,22.26 mmol), rh (CO) ₂ acac (3.3 mg,0.0128 mmol) and biphospos (27.3 mg,0.0347 m)mol). By H ₂ The vessel was purged with/CO (1:1, 4X5 bar) and heated under vigorous stirring at 90℃and 10 bar synthesis gas pressure for 24 hours. After cooling and depressurization, GLC analysis of the crude product showed total conversion and the presence of 3- (4, 4-dimethyl-1- ((trimethylsilyl) oxy) cyclohexyl) propanal (92.2%) and ((1-ethyl-4, 4-dimethylcyclohexyl) oxy) trimethylsilane (6.8%).

3- (4, 4-dimethyl-1- ((trimethylsilyl) oxy) cyclohexyl) propanal:

¹ H-NMR(600.15MHz):δ0.12(s,9H,Si(CH ₃ ) ₃ ),0.88,0.93(2x s,6H,C(CH ₃ ) ₂ ),1.15-1.22(m,2H),1.36-1.49(m,4H),1.55-1.62(m,2H),1.82(t,J＝7.6Hz,2H,H-3’),2.48(t,J＝7.27Hz,J _H-H ＝1.69Hz,2H,H-2’),9.67(t,1H, ² J _1,2 ＝1.60Hz)。

¹³ C NMR(125MHz,CDCl ₃ ):δ2.6(q),28.4(q),29.6(s),32.3(t),34.2(t),35.7(t),38.7(t),74.9(s),203.0(d)。

example 24

acid/Lewis acid screening for conversion of dioxolane acetate to unsaturated dioxolane

For acid/Lewis acid screening, the substrate acetic acid (1- (2- (1, 3-dioxolan-2-yl) ethyl) -4, 4-dimethylcyclohexyl ester, 216mg,0.8 mmol) was heated in the presence of a catalyst (acid, lewis acid) in 1mL of anhydrous toluene in a sealed glass bottle (1 hour at room temperature, 1 hour at 50 ℃,1 hour at 120 ℃,2 hours at 120 ℃). The conversion of the starting material to the desired product ((2- (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane, 3- (4, 4-dimethylcyclohex-1-en-1-yl) propanal (minor product)) was determined by GC analysis.

The results obtained are shown in Table 11.

Table 11: acid/Lewis acid screening for the conversion of 1- (2- (1, 3-Dioxolan-2-yl) ethyl) -4, 4-dimethylcyclohexyl acetate to (2- (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-Dioxolan

/>

1) Internal/external ratio (2- (2- (4, 4-dimethylcyclohex-1-en-1-yl) ethyl) -1, 3-dioxolane (internal)/2- (2- (4, 4-dimethylcyclohexylidene) ethyl) -1, 3-dioxolane (external).

Claims

1. A process for the preparation of a compound of formula (I),

2. The method of claim 1, wherein R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently represents a hydrogen atom or C _1-3 An alkyl group.

3. The process according to any one of claims 1 to 2, wherein the compound of formula (I) corresponds to formula (I'),

the compound is in the form of any one of its stereoisomers or mixtures thereof, wherein each R ¹ And R is ² Has the same meaning as defined in claim 1;

And the compound of formula (II) corresponds to formula (II'),

the compound is in the form of any one of its stereoisomers or mixtures thereof, each X, R ¹ And R is ² Has the same meaning as defined in claim 1.

4. A method according to any one of claims 1 to 3, wherein R ¹ Is C _1-4 Alkyl or C _2-4 Alkenyl groups.

5. The method of any one of claims 1 to 4, wherein R ¹ Is methyl.

6. The method of any one of claims 1 to 5, wherein R ² Is hydrogen atom, C _1-3 Alkyl or C _2-3 Alkenyl groups.

7. The method of any one of claims 1 to 6, wherein R ² Is methyl.

8. The method according to any one of claims 1 to 7, wherein the method comprises the steps of:

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein X, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ The same meaning as defined in claim 1;

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein X, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined in claim 1, and R ^a And R is ^b Each independently represents C _1-4 Alkyl, or R ^a And R is ^b Taken together represent C _2-6 Alkyldiyl, preferably R ^a And R is ^b Taken together represent (CH) ₂ ) _n A radical, wherein n is 2 or 3;

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined in claim 1, and R ^a And R is ^b Has the same meaning as defined above; and

d) Deprotection of the acetal groups to give compounds of formula (I).

9. The method according to any one of claims 1 to 7, wherein the method comprises the steps of:

a) Elimination of the OX 'group of the compound of formula (II'),

the compound is in the form of any one stereoisomer or a mixture thereof, wherein X' is a hydrogen atom, C _1-3 Alkyl, C _2-3 Alkenyl, benzyl or a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group; wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ Has the same meaning as in claim 1;

to obtain a compound of formula (VI),

the compound is in the form of any one of its stereoisomers or mixtures thereof, wherein R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Has the same meaning as defined in claim 1; and

10. The process according to any one of claims 1 to 9, wherein the hydroformylation is carried out in the presence of a rhodium catalyst.

11. The process according to any one of claim 1 to 10, wherein the preparation of the compound of formula (II) comprises a step of reducing the compound of formula (VII),

the compound is in the form of any one of its stereoisomers or mixtures thereof, wherein X represents a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group; each R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently represents a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group; or R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Two groups of (B) together form C _3-8 Cycloalkyl or C _5-8 Cycloalkenyl, the other groups having the same meaning as defined above;

12. A compound of the formula (III),

13. The compound of formula (IV'),

the compound is in the form of any one of its stereoisomers or mixtures thereof, and wherein X' is a hydrogen atom, C _1-3 Alkyl, C _2-3 Alkenyl, benzyl or a C (O) R group or Si (R') ₃ A group wherein R is a hydrogen atom, C _1-4 Alkyl, C _1-4 Alkoxy or phenyl, R' are each independently C _1-4 An alkyl group; each R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently represents a hydrogen atom, C _1-6 Alkyl or C _2-6 Alkenyl groups, each optionally substituted with hydroxy or C _1-3 An alkoxy group; or R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Two groups of (B) together form C _3-8 Cycloalkyl or C _5-8 Cycloalkenyl, the other groups having the same meaning as defined above; r is R ^a And R is ^b Each independently represents C _1-4 Alkyl, or R ^a And R is ^b Taken together represent C _2-6 An alkanediyl group; with the proviso that 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4-isobutyl-2-methylcyclohex-1-ol, 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4-isopropyl-2-methylcyclohex-1-ol, 1- (3, 3-diethoxypropyl) cyclohex-1-ol, 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4- (tert-butyl) -2-methylcyclohex-1-ol, 1- (2- (1, 3-dioxolan-2-yl) ethyl) -4- (tert-butyl) cyclohex-1-ol and 1- (2- (1, 3-dioxan-2-yl) ethyl) -4- (tert-butyl) cyclohex-1-ol are excluded.

14. The compound of the formula (V'),

15. A compound of the formula (IX),